Aging of HIV-Infected: a explosive and underestimated phenomena being ignored, needs attention - special support services for patients & clinics needed-lack of federal/state response - HCV too - Commentary by Jules Levin
"Community Perspectives: "A call to action: What should our research, care, education and social support priorities be?"
Jules Levin, NATAP
HCV is a Comorbidity. I have had HIV for about 35 years, I am 67 years old now, I had hepatitis C like at least 30% of people with HIV in the USA. That 30% is deceptive because as many as 80-90% with a history of IDU have HCV so in HIV that comprises a big proportion of HIV-infected people particularly inner city, African-Americans & Latinos. Although I was cured back in 2001 I have been doing an MRI every 6 months since and will continue doing to make sure HCC does not develop and its important for continuing to monitor other liver conditions, that is the Recommendation. At $1500 per MRI that is quite a price for the healthcare system to pay for not treating HCV early ! - $3000 a year for 16 years = $48,000, more than the price of a cure. I was perhaps the first peg interferon coinfection cure back in 2001. Liver disease and infection with hepatitis C (HCV) are also common HIV comorbidities. Fatty liver is all too often overlooked in HIV+, as many with elevated liver enzymes (ALT, AST) are often written off as normal without understanding by clinicians this could reflect fatty liver and steatosis or NASH. The risk for sexual transmission increases in the presence of an STD and HIV. HCV is similar to HIV and aging - dismissed by federal officials. Although we have high cure rates, as high as 95-100% with new treatments access to treatment is restricted to some by state Medicaids and there is little federal support to challenge this and for hepatitis C screening and linkage to care. In fact the federal government is complicit in allowing state Medicaids to restrict access.
We are underestimating and I would say essentially ignoring the impact of aging in the USA and globally. 50% with HIV are over 50; 20-25% are over 60, soon 50% will be over 60 years old; 16-25% are 45-49, but of particular note 80% are over 45.
In 2015 health officials reported 52% were over 50 in key major cities and states - NYC, SF, Florida and Boston - but more noteworthy they reported 21-25% were over 60 and 16-24% were 45-49. 9
We are essentially ignoring the aging of patients, they are forgotten. The first generation still living with HIV are aging into their 60s and 70s. They typically had low CD4 nadir, started HAART at low CD4s as treatment back then was deferred until CD4 counts were low, and had treatment experience prior to protease inhibitor therapy with the old more harmful nucleosides: AZT, d4T, ddI, ddC. Despite funding for research to find a medical intervention [an anti-inflammatory for HIV+ aging], which may or may not in fact find a medical intervention, there is no national discussion or attention paid to the daily needs of these patients, their daily healthcare and living circumstances, and for the clinicians who provide their care. This is akin to the generation of HIV-infected who back in the earlier days from the mid 1990s through 2010 developed body changes called lipodystrophy. Millions of dollars were spent on research with no medical solutions discovered nor was there ever a real understanding developed of the causes, so this group of now aging patients were essentially forgotten. There is no more discussion or attention paid to this large group of patients. Similarly, we are not addressing the daily living needs affecting those who are older and experiencing the impact of premature aging, and the real impact of the diseases which we know HIV can make more severe: frailty, worsening cognitive impairment; the affects of worsening osteoporosis: falls and consequent fractures; heart disease; cancers; and worsening capacity to perform normal daily living activities including mobility.
Italian researchers projected at the Aging Workshop in NYC in September 2016: In 15 years time 75%will be frail, the most frail HIV population will increase from 24% [now, 2016] to 48%, "that 34% will be frail and disabled in 15 years and will need to be in a home, 30% will experience a fall in 15 years, up from 20% now, that the total direct cost increases two-fold moving from the <40 years age strata of HIV-infected patients (US$10,588.45) to those older than 60 years (US$21,280.72)". 13
It has been accepted that there is a 10-year shift due to 'premature aging, that HIV+ are 10 years ahead in the aging process compared to HIV-neg, that HIV+ are aging 10 years more quickly than HIV-negs. 10
Of note Ances et al published in JAIDS in 2012 on neuroimaging of HIV-infected and uninfected and said "In our cohort, HIV led to approximately 17 years of aging of the brain....HIV and aging independently increase brain vulnerability.....our results suggest that a decrease in brain integrity within older HIV+ participants, even those taking HAART, may indicate that these individuals have increased vulnerability for subsequently developing neurodegenerative disorders....pathological changes continue to persist, primarily in subcortical regions, despite HAART. 11
Non-AIDS deaths now account for 50%: with 16.6% due to CVD, 23.5% to non-AIDS malignancy, and 14.1% due to liver-related (data from 13 HIV cohorts 1996-2006; Antiretoviral Therapy Cohort Collaboration, CID 2010). 12
We are ignoring the true impact of aging in HIV and as well it's affect on healthcare economics and the impact of multi-comorbidities and polypharmacy in older HIV+ - often with 4-6 comorbidities and taking 12+ comedications. It already is very difficult to manage but will become increasingly unmanageable with increasing polypharamcy, and increasing multicomorbidities. Complicating the situation further is the potential for non-adherence to ARTs complicated by the presence of cognitive impairment, and increasing numbers of drug-drug interactions between ARTs and medications patients take for comorbidities. Unless we begin to truly address this now it will come back to haunt federal officials and decision makers; this is a global problem that will worsen here in the USA and globally.
HIV-infected have more comorbidities than HIV-negative individuals. 6 As HIV-infected are aging the numbers of comorbidities are increasing for each patient. Today 40-50% HIV-infected have 3 or more comorbidities, and the polypharmacy of these patients is that they are often taking 7-12 medications for treatment of their multiple comorbidities and taking ARTs too. As well there appear to be racial disparities with Male African American and Hispanic Medicare beneficiaries were more than 3 times as likely to have HIV for each level of the chronic condition index as compared to white females with the same number of chronic conditions, and Blacks & Latinos had on average 4-fold increased risk for the comorbidities listed here compared to Whites, and also 3-4 times more likely to have 5 or more comorbidities compared to Whites. (8)
Of note reported by the AgehIV Cohort for HIV-infected with largely suppressed HIV viremia on cART in the Netherlands as HIV-infected had significantly higher prevalence of comorbidities compared to HIV-uninfected. 50% over age 60 had 2 or more comorbidities, and for patients over 65 70% had 2 or morbidities and 40% had 3 or more comorbidities. The numbers of comorbidities HIV-infected had increased with age with patients over 60 and more even over 65 experiencing increasing numbers of comorbidites, while HIV-uninfected had less numbers of comorbidities and as they aged the numbers of comorbidities did not increase nearly as much compared to HIV-infected: HIV+ - 43% had hypertension, 30% COPD, 20% fracture/osteoporosis, 12% cancer, 9% chronic liver disease, 5% reduced renal function, and 5-7% various types of heart disease and diabetes. As these patients age it will be increasingly difficult to manage their multiple comorbidities and polypharmacy.
In an analysis of over 9,000 patients presented at HIV Glasgow 2016 (7), for treatment-naïve patients at an average of only 40 (SD-12) 19% had hypertension, 18% lipid disorders, 11% depression, 8.8% anxiety, 7.8% diabetes/abnormal glucose. 7 In German Cohorts TRIUMPH and DOL-ART presented at Glasgow 2016 where average age was 39 years old (29-48) 6-% of treatment-naïve study patients were taking antihyperintensives, 3.7% to 5.1% were taking anti-depressants, in contrast treatment-experienced study patients with average age of 45 (35-53) 14.9% to 19% were taking antihyperintensives and 11.1% to 11.9% were taking antidepressants, a doubling in the number of patients taking these two classes of medications.(1) The VA Aging Cohort reported at IDSA in 2013 reported HIV+ vets with average age around 55 around 70% had any comorbidity and around 15% were taking 7-9 medications and 13% taking 10 or more medications and found the number of medications was associated with mortality: "Mortality risk was linearly associated with number of medications crossing significance (p=0.03) at 6 or more. With each medication beyond five, risk of mortality increased 10% in unadjusted and 5% in adjusted analyses. Those on > 5 medications had a 30% higher risk of mortality". (2) Perhaps the most revealing is the SCOPE San Francisco Cohort. 4 Average age was 57 (54-62) with 15.4% 60-65 and 19.4% over 65 years old, average number of comorbidities was 4 (3-6), and the number of nonantiretroviral medications was 9 (6-12). 4
In a Medicare analysis HIV+ beneficiaries were approximately twice as likely as those without HIV infection to have chronic condition flags indicating hypertension, hyperlipidemia, ischemic heart disease, rheumatoid arthritis/osteoarthritis, or diabetes. Blacks & Latinos had on average 4-fold increased risk for the comorbidities listed here compared to Whites, and also 3-4 times more likely to have 5 or more comorbidities compared to Whites.
The Aging and HIV problem is an explosive situation, it is already devastating to many patients and will get much worse.
Increasingly many more older patients as they get into their mid 60s are unable to perform ordinary daily activities and functioning, these patients are already disabled and this will get worse for these individuals and across the board for patients on a whole, both here in the USA and globally in the future.
The impact of this problem is truly underestimated, it receives much less attention than it deserves, it is misunderstood by many, and is and will have a devastating affect on patients and HIV healthcare, across the field in the USA and will have equal impact in Western countries and then in developing countries too.
Although most with HIV in the USA are older and affected by this there is no real attempt to deal with the problem, it has been pushed aside by the politics of HIV. The federal government has always responded to political expediency. Federal HIV/AIDS leadership has yet to have real discussion about what are all the key and relevant issues and how can we begin to address them, its not only to have a interventional medical research agenda. In the USA the federal government spends domestically tens of billions of dollars of taxpayer money on HIV. It costs much more as a patient ages and the immune system worsens and comorbidities get worse to pay for care and treatment for these comorbidities. Older aging patients need support services and their clinicians need education and support services as well. A recent study presented at the Aging Workshop in Washington DC in September 2016 found 50% with comorbidities went untreated with therapy, despite that multi-comorbidity was highly prevalent with 38% to 56% had diabetes, hypertension and dyslipidemia. The average age was 50 (39-68) and 18% were over 60. This is in a cohort of 7,000 HIV-positive adults with HIV in Washington DC, an aging citywide contemporary cohort of largely non-Hispanic black HIV outpatients. 14
In HIV 65 (years old) is the new 85, but in the normal world 65 is the new 55 because among the HIV-negative normal population people are living longer, heart disease is better managed, and there is so much more focus on exercise and good diet in the general population. The exact opposite is happening in HIV. It is understood and accepted and supported by research that the brain and other organ systems are aging faster in HIV+, with studies finding HIV+ aging can be variously 10 to 20 years faster compared to HIV-negatives.
The giddiness of the early days of ART & HAART are gone. Yes when protease inhibitors came out in 1996 I certainly was elated and convinced we had found the answer. For years and still now we say things like people with HIV are living so much longer now and we have survival studies that project estimations of long lives, even if just short of life expectancy compared to HIV-negatives. But these studies are damaging in that they create the illusion of what is really going on. Many do not realize these studies are estimations and projections that do not consider how comorbidities and aging will affect older HIV+. This creates a complacency regarding aging & HIV. These studies are unable to truly consider these future events; in fact, it is very difficult to predict what will happen. These studies are damaging because they lull people into thinking older patients are doing well and will have life expectancies that are not that much worse than HIV-negatives.
The truth is many older HIV+ are experiencing much more comorbid conditions - bone disease and fractures, heart disease, abnormal lipids, kidney disease, brain and neurologic disorders, diabetes, cancers, frailty, and HCV (HBV too) - than HIV-negative individuals - this is very often happening at earlier ages for many HIV-positive individuals compared to HIV-negative individuals. HIV is a devastating virus, it is not just an ordinary virus. It gets into the brain within days of transmission and remains there forever despite successful viral suppression. As we age with HIV and the immune system ages brain and cognitive disorders worsen. The immune system is crippled by HIV. For most at younger ages often brain & cognitive function abnormalities are asymptomatic, but as people age past 60-65 I suspect it will become more symptomatic, in fact we have no real-time research reporting now brain related symptomology in older aging patients and not to mention, will these older HIV+ be more susceptible to brain disorders like alzheimers, a real question yet to be addressed. Shortly after infection HIV causes senescence which for normal people does not usually occur until they reach around 65. We know from the early days of HIV that despite normalization of CD4 there remain gaps in this immune improvement, usually the CD4:CD8 ratio remains terribly inversed. Many with HIV had or continue to have lifestyles that contributed importantly to damaged immunity, illicit drug use - heroin, cocaine, and methamphetamines damage the immune system which contributes to this problem we in HIV have - much more comorbidities, earlier onset of many of these diseases, and acceleration of aging. This last comment I made has been somewhat controversial with a small minority of researchers saying its not acceleration but it is accentuation. This is another damaging point of view. First, immune decline and senescence is accelerated in HIV, for many, research is convincing on this. Some comorbidities at least are accelerated, but everyone agrees comorbidities are more prevalent in HIV, will increase in older patients, and HIV-positive individuals have more, sometimes much more, prevalence for comorbidities and polyphramacy. Second its an irrelevant argument in the face of the what is happening to patients do to take up space discussing this is misleading damaging to the cause and problem.
Not only are many patients with HIV these days experiencing increased cognitive impairment as they age into their 50s and worsening into their 60s, they are also experiencing increased falls and fractures, and increased frailty. They are also experiencing increased disability and inability to perform normal daily functioning. This is a recipe for disaster ahead. The costs for polypharmacy, the many comedications patients are taking, are overall more expensive than the ART regimens. Many patients can be taking as many as 8 to 12 additional pills or medications besides their ART medications. The polypharmacy costs will only increase with time as more patients age. A retrospective cohort at Northwestern University in Chicago reported on 100 patients - 35% (n=35) with average age 61 (55-66) were taking an average of 14 medications (11-17) including ARVs, 12 not counting ARVs. 65 patients were taking an average of 6 medications (4-8) and 4 (2-6) not counting ARVs. (3)
It was about 10 years ago I recognized the aging and HIV problem. I organized an ACTG Ad Hoc group of key researchers and an educational lecture day on bone disease at an ACTG meeting with key ACTG bone expert speakers, which was very well attended and received good reviews. Out of that meeting the ACTG Bone Subcommittee was formed. I started to educate the broad affected community and stakeholders through the NATAP list serves and website about the aging problem, it took two years to have reasonable impact in convincing the field and stakeholders including patients, advocates, clinicians, doctors, researchers, industry, and government officials that there is a problem. I contacted Bob Eisinger and Jack Whitescarver at the OAR (Office of AIDS Research) along with a small group of advocates with several key requests. I was impressed Jack and Bob had already agreed to a letter from a few key advocates sent to them by letter - to form a panel in which I participated who reviewed the research needs in aging and after 1 year issued a paper that was published, which I requested them to publish and they did. But these were only a research agenda. I asked the OAR to help dedicate NIH funding to aging/HIV research and they did again without a hesitation.
Research continues and the search for anti-inflammatories- for which it is duly felt inflammation contributes greatly to the aging problem - persists but will this provide solutions? Maybe, maybe not.
It is not only the health comorbidities suffering patients will endure but in a way more important is the social, real-life impact of HIV & Aging - we are seeing & it will get worse - increased depression & stigma, suicidal ideation, substance abuse, housing and income problems, for some complete disability to the point of being unable to shop, visit the doctor, or perform very ordinary daily functioning like cooking & showering - perhaps increased non adherence which would introduce a greater dimension to the problem of aging & HIV.
The aging problem is complicated and real for patients. It is a complicated problem that I think is not well appreciated and understood by many, and unfortunately is therefore relegated to secondary seriousness.
The ignoring of these problems is very similar to what is going on in HCV. Unlike HIV we have a cure for HCV. Although I had to suffer peg interferon for 2 years today patients can take a 12-week tolerable and safe therapy with cure rates of up to 100%. It is estimated that for an HIV patient on ARTs it can cost about $400,000 just for HAART for 30 years, not including the doctor visits, care for comobidities and other associated costs, including healthcare infrastructure, which altogether might cost $500,000 or more over 30 years. We pay for all this. The federal government spends $20 billion a year domestically just on Medicaid & Medicare for HIV. Last year President Obama said 'lets fund finding a cure for HIV', and miraculously shortly thereafter the NIH announced it was going to dedicate over $100 million to cure research. Are all these expenses cost effective? Of course many of us would say yes. But we can cure HCV and save all the much greater downstream costs related to HCV that would incur without successful HCV cure. Yet The White House and Congress refuses to fund unfettered HCV screening and treatment, they are complicit with State Medicaids restricting access to these curative therapies unless a patient has late stage disease despite that the prices for these HCV drug therapies have been slashed by 50% to 60% to around $35,000 or even much less for the VA (Veterans Administration). Federal officials refuse to adequately address all the needs of aging & HIV, despite that this will be very costly and devastating problem. Why? HIV politics, and healthcare politics ! We could eradicate HCV in the USA because we have curative treatment yet the White House & Congress refuse to address this problem in any sort of real way, essentially its being ignored.
So what do we need to do? We need a National Discussion of Aging and HIV where we can put all the challenges on the table and design a strategy and dedicate a leader and full funding to the implementation of this strategy. Just like the NIH is holding national meetings on finding a cure with dedicated budgets and research and commitment, we need the same commitment to Aging and HIV.
As I mentioned over 50% with HIV in the USA are over 50 YO and soon 60% & then 70% will be over 50 and soon 50% will be over 60, 65. Who is supposed to decide how taxpayer money is spent on HIV, the elite decision makers, or the real people suffering with HIV. Even if a cure for HIV were found tomorrow the damage to the immune system and the organ systems will have already been done, and a cure will not undue the damage, older aging patients will still suffer the ravages of the aging & HIV phenomena. Still finding an HIV cure may or my not happen, even if it does happen it could take 10 years, maybe 20 years, if ever. Of course we should continue the search for a cure for HIV but not to the exclusion of adequately addressing the aging/HIV problem. The suffering of older HIV+ is real, its here, it will get worse, should elite federal officials and others decide where HIV taxpayer money should go or should patients have more say. Of course we patients should be able to have more control over how this taxpayer money is spent, and we don't, and again over 50% with HIV are over 50 YO & soon 50% will be over 60 YO. This is similar to lipodystrophy. We spent tens of millions of dollars on lipodystrophy research without ever finding a solution and have since ignored lipodystrophy & those suffering with its lingering affects who are NOW the older aging HIV+; we are spending a ton of research money on trying to find anti-inflammatories & understand aging pathogenesis and we should !! We need to address all the other problems older patients are facing - the challenges to living - depression, daily living disabilities, etc - in addition the scope and direction of anti-inflammatories research and the healthcare costs related to aging with HIV. We need to a program of special support services for older aging patients, and for the clinics and clinicians facing these challenges with the patients. We need a dedicated program and strategy just like for HIV cure, aging is as great a problem and burden for patients if not greater problem. All too often clinicians and doctors are not addressing comorbidities. In Washington DC 50% of patients are not receiving care & treatment for their comorbidities. It is very difficult to navigate the complicated healthcare system to address multiple comorbidities and to see numerous specialists particularly for individuals with limited health literacy. Doctors and clinicians and clinics need the training and support to provide good care; patients need the education to understand the problem - to take preventative measures - exercise, good diet, healthy lifestyle; patients need special support services to deal with all the social and health challenges related to HIV and aging that I outlined above. We need a National Discussion on Aging & HIV; we need a strategy to address all the needs; we need a dedicated NIH Aging & HIV federal office with a presence in The White House, and we need a budget that reflects the importance and gravity of this problem. We need to bring into this Aging/HIV Office-Leadership all the other relevant NIH Institute leaders including the National Institute of Aging and to have full gravity & impact. The White House & the NIH Director need to support this effort & be involved.
1 Baseline characteristics of the TRIUMPH and DOL-ART cohorts: Use of Triumeq® (DTG/ABC/3TC) or other DTG-based ART in routine clinical care in Germany - Comorbidities/Polypharmacy. Heuchel T HIV Glasgow 2016.
2 HIV+ Individuals on ART Are At Risk of Polypharmacy: More Medication Increases Mortality IDSA 2013 EJ Edelman http://www.natap.org/2013/IDSA/IDSA_11.htm
3 Wilcox ML, Cottreau J, Mancuso T, et al. Evaluating the effect of polypharmacy on outcomes in HIV-infected patients age 50 and older. IDWeek 2016, October 26-30, 2016, New Orleans. Abstract 1496
4 Geriatric Syndromes in Older HIV-Infected Adults; JAIDS December 2014; M Greene et al..
5 Giovanni Guaraldi et al. Clinical Inf Disease 2008; 47:250-7.
6 Cross-Sectional Comparison of the Prevalence of age ‐ associated comorbidities and their risk factors between HIV-infected and uninfected
individuals: the AGEhIV Cohort Study. Clin Inf Dis 2014; Schouten et al.
7 First-Line Antiretroviral Treatment Characteristics Among HIV-Infected Patients With and Without Comorbidities. HIV Glasgow 2016. Girish Prajapati et al.
8 Chronic health conditions in medicare beneficiaries 65 years and older with HIV infection. AIDS July 2016 Friedman, Eleanor E
Projecting CVD risks in HIV-infected individuals in the US: competing risks and premature aging. Losine et al CROI 2013
11 Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures JAIDS. Jan 2012 Ances et al
12 data from 13 HIV cohorts 1996-2006; Antiretoviral Therapy Cohort Collaboration, CID 2010
13 Future challenges for clinical care of an ageing population infected with HIV: a "geriatric -HIV" modelling study. Guaraldi G et al. 18th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV, Sept 12-13, 2016, New York, NY
14 Levy ME, Greenberg AE, Hart R, Powers Happ L, Hadigan C, Castel A. High burden of metabolic co-morbidities in a citywide cohort of HIV outpatients: evolving health care needs of people aging with HIV in Washington, DC. 7th International Workshop on HIV and Aging, September 26-27, 2016, Washington, DC