Clinical and Health Affairs
Peering into the Future: Searching for Answers to Old and New Questions about HIV/AIDS
By W. Keith Henry, M.D., Ogechika K. Alozie, M.D., M.P.H., and Shulamith Bonham, M.D.
Abstract
The success of the scientific quest to understand and treat HIV/AIDS since it was first identified in the United States nearly 30 years ago merits celebration; yet new, unexpected problems continue to develop as old ones persist. The significant benefits of combination antiretroviral therapy (cART) have contributed to the perception that the global or national threat posed by HIV/AIDS no longer exists. The persistent high levels of new HIV infections in the United States (56,000/year) and the world (2.7 million/year) underscore how much work remains to be done. This article highlights seven key questions that will define the scientific, clinical, and policy efforts to combat HIV/AIDS in the decades ahead.
When the first AIDS patients were identified in Minnesota in 1982, AIDS was a frightening and uniformly fatal condition. No cause had yet been identified and no treatment was available. It quickly became apparent that the disease was caused by a blood-borne and sexually transmitted infectious agent and that it could wreak havoc within certain populations (initially men who have sex with men [MSM], people with hemophilia, and recipients of contaminated blood transfusions). When the first HIV clinic in Minnesota was established in St. Paul in 1985, most of the clinical action was hospital-based, the number of patients seen in the clinic was held in check by the high mortality rate (at one point averaging nearly one death per week and one new patient per week).
Over the next decade, the situation changed dramatically. The human immunodeficiency virus was identified as the etiologic agent, setting off an explosion of basic science and clinical research.1,2 Improvements in identification and treatment of AIDS-related complications were followed by the development of antiretroviral drugs (ARVs) targeting key steps in the lifecycle of HIV. Because of the following three developments, 1996 was a pivotal year. First, a blood test was developed that directly measured the level of HIV RNA in plasma. That allowed for fast screening of potential drugs and rapid assessment of effectiveness in clinical trials. Second, drugs from two new drug classes became available (non-nucleoside reverse transcriptase inhibitors [NNRTIs] and protease inhibitors [PIs]). Finally, clinical studies showed that use of three antiretroviral medications (two of the older nucleoside/nucleotide reverse transcriptase inhibitors plus either an NNRTI or a PI) resulted in major reductions in AIDS-related morbidity and mortality. This amazing breakthrough was recognized by Science magazine in 1996 as the scientific breakthrough of the year.3
Use of multiple medications or highly active antiretroviral therapy (HAART), also termed combination antiretroviral therapy (cART), resulted in an immediate reduction in deaths (by nearly 90%) and recovery to health of patients who were terminally ill with AIDS. Although effective, the early HAART regimens were often complicated and caused numerous side effects. Over the next decade, HAART regimens improved. Today, more drugs and more classes of drugs are available, and the side-effect profile of antiretroviral therapies has improved.
This has contributed to the perception that the threat posed by HIV/AIDS no longer exists. However, advances in the treatment of AIDS have not been matched in the prevention arena. The persistent high levels of new HIV infections in the United States (56,000/year) and the world (2.7 million/year) underscore the fact that much work remains to be done. This article highlights key questions that will define the scientific, clinical, and policy work that needs to be done to combat HIV/AIDS in the decades ahead.
What is the Scope of non-AIDS HIV Disease?
During the first 10 years of the AIDS epidemic, the medical community became familiar with the concept of AIDS-defining conditions. These are the opportunistic infections or cancers seen in HIV-positive persons with severe immune damage. Much of the focus of the early ART studies was evaluating the impact of ART on the number and lethality of these conditions. As treatment improved and clinicians gained experience with HIV-positive persons who had higher CD4+ counts (ie, greater than 200 cells/mm3), evidence started to suggest that people who were HIV-positive were at greater risk for cardiovascular disease, a wide range of cancers, kidney disease, and liver disease than would be expected in the general population. Furthermore, the risk for those conditions (termed non-AIDS HIV-related diseases) appears to increase with decreasing CD4+ counts. This phenomenon was clearly observed in the SMART study, wherein participants who stopped HAART when their CD4+ counts were greater than 350/mm3 quickly began to experience higher rates of AIDS and non-AIDS events with higher mortality compared with persons continuing HAART.4
Data about non-AIDS HIV-related disease were lacking in the first 10 years of ART studies, when the focus was AIDS and therapy was less effective and often involved persons with relatively low initial CD4+ counts. For HIV-positive patients on cART with CD4+ counts greater than 350 cells/mm3, non-AIDS events are the major cause of morbidity and mortality, with heart disease and cancer leading the list. People who are HIV positive are at increased risk for cardiovascular disease because of traditional risk factors (ie, elevated lipids, high blood pressure, aging, diabetes, and smoking), cART-related factors (lipid and glucose/insulin abnormalities), and HIV-related factors (ie, a decrease in HDL cholesterol, an increase in triglycerides, immune activation, increased thrombosis and fibrinolysis, and endothelial dysfunction).5
Data from several CDC-sponsored cohorts indicated an increased incidence of many types of non-AIDS-defining cancer (anal, vaginal, Hodgkin’s lymphoma, liver, lung, melanoma, oropharyngeal, leukemia, colorectal, and renal) from 1992 to 2003 compared with that in the general population.6 The DAD Study in 2008 reported a link between the severity of immune suppression and the risk of death from both AIDS-related and non-AIDS-defining malignancies.7 There are a number reasons why people who are HIV positive may be at increased risk for malignancies. One is that they may engage in behaviors such as smoking and alcohol and drug abuse that can lead to increased exposure to oncogenic, sexually transmitted, or blood-borne viruses such as human papilloma virus, hepatitis B and C, Epstein-Barr virus, and human herpes virus.7 Another relates to chronic mild-to-moderate immune deficiency and possible concomitant decreased immune surveillance.
HIV-related renal disease often is caused by a direct effect of HIV on renal tissues (HIV nephropathy), while HIV-related liver disease often involves a complex interplay between viral hepatitis, HIV, and use of drugs or alcohol that exacerbate liver damage. For all of these non-AIDS HIV-related conditions, data quantifying the risk by CD4+ strata and the effectiveness of ART or very early treatment (at CD4+ counts greater than 500/mm3) are scant. This will be a focus of future research efforts that will bear highly on treatment recommendations.
Does HIV Infection Accelerate Aging?
Data from a limited number of studies have raised concern that HIV infection, even if it is well-managed, could contribute to an acceleration of the aging process. An example of that concern is the now well-documented association between HIV infection and accelerated bone loss. HIV infection should be considered a risk factor for osteopenia/osteoporosis, although it is not yet so identified in the major guidelines. Data from the SUN study showed an osteopenia rate of 52% in a cohort of HIV-positive persons on cART versus 29% in a matched cohort from the NHANES study; the corresponding rates of osteoporosis were 10% and 1%, respectively.8 Multivariate analysis of risk factors for osteoporosis noted increased risk for people who are 45 years of age and older and for those who have been infected with HIV for a long time. Although cART has been shown to decrease the risk for HIV-related dementia, there appears to be a significant subset of patients on cART who have mild-to-moderate neurocognitive impairment, with some patients developing impairment even after starting cART. This may be partially the result of ongoing HIV replication in the central nervous system because of poor drug penetration into that compartment.9 In addition, HIV infection itself may cause brain aging. One study suggests that HIV infection translates to a 15- to 20-year increase in brain aging.10
Frailty in the aged involves loss of muscle mass, weight, and energy; slower muscle performance; and limited physical activity. Increasing frailty in the aged is linked to a variety of processes including dysregulation of the immune system and inflammation as well as anemia, hormone deficiencies, and sarcopenia. Because of the apparent overlap between the causes and manifestations of frailty in the general and HIV-infected population, one study assessed frailty in a cohort of untreated HIV-positive persons that was matched with a cohort of uninfected men.11 HIV infection was strongly associated with frailty, with the rate for a 55-year-old HIV-positive man infected for less than four years similar to that of uninfected men older than 65 years of age. In a follow-up study, CD4+ T-cell count was closely linked to the level of frailty.12 Combination ART is likely to favorably affect the development of frailty, but no studies have assessed that relationship.
Can ART Be Further Improved?
Although many HIV regimens now involve once-daily dosing with one to four pills, problems with ART remain. The popular NNRTI efavirenz-based regimens often have central nervous system side effects and a low barrier to resistance, and are not recommended for use by pregnant women. New drugs in the NNRTI class such as rilpivirine are being developed to rectify many of those issues. Drugs in the protease inhibitor class generally use a ritonavir boost (a low dose of ritonavir that inhibits liver clearance of other PIs, improving pharmacokinetic characteristics). Ritonavir has a dose-related effect on plasma lipids and gastrointestinal symptoms and has been coformulated with one other PI (with lopinavir in the drug Kaletra). A nonritonavir PI-boosting drug now known as GS-9350 is under development in order to address many of the side effects of ritonavir.13
Patients with complex treatment histories, drug intolerance, resistant strains of HIV, or problems adhering to a treatment regimen often require ARV drugs from new classes in order to achieve full levels of viral suppression. Drugs in the CCR5 inhibitor class (miraviroc, now available, and vicriviroc, which is in development) appear to be well-tolerated and are potentially useful in a number of treatment settings perhaps including initial therapy. The most promising new class of ARVs is the integrase inhibitors. Raltegravir is already available and has recently been approved for initial therapy as well as for patients with drug-resistant virus strains. As a class, integrase inhibitors have been well-tolerated, have few drug interactions, can potentially be coformulated, are highly potent, and appear lipid/fat friendly. One area of uncertainty for the class is the barrier to resistance. Promising new drugs in the class include elvitegravir and GSK 1349572. Elvitegravir is being developed in a four-in-one pill (another one-pill, once-a-day treatment option) that offers a glimpse into the future of cART.
Should Everyone with HIV Be Treated?
Current treatment guidelines recommend that HIV-positive persons should be treated before their immune system is severely damaged (currently, the threshold is before their CD4+ count falls below 350 cells/mm3), which is when the risk for AIDS-related complications begins increasing. There is clearly an argument to be made that early use of cART would likely decrease the risk for non-AIDS HIV-related conditions, thus potentially improving the overall health of individuals. There is also the theoretical benefit that early widespread use of cART would result in decreased HIV transmission and thus reduce the cost of HIV to society.
Data to support early use of cART comes mostly from large observational cohort studies.14,15 The cost benefit of early use of cART would likely decrease with increasing CD4+ counts; but good quantifying data are lacking. The START trial, an international study being conducted by the University of Minnesota (with a site at Hennepin County Medical Center), is now randomizing 4,000 HIV-positive patients who are treatment naïve and have CD4+ counts greater than 500 cells/mm3 to either immediately begin cART or undergo careful observation until their CD4+ count is less than 350 cells/mm3 (Figure). During the next four to five years, it is hoped that the results will inform clinicians and policymakers about whether to recommend cART even for persons with high CD4+ counts.
Will We Be Able to Sustain Treatment for All Who Need It?
As HIV disease becomes a chronic condition that can be treated on an outpatient basis, issues related to primary health care access and payment in the United States become germane. A crucial issue is the capacity of the health care system to provide uninterrupted access to care and drugs. It is estimated that 1 million persons in the United States are infected with HIV, of whom 480,000 need antiretroviral therapy; of those, only 340,000 are under a clinician’s care, with 268,000 receiving antiretrovirals.16 Also, an estimated 25% of HIV-infected patients in the United States are not yet aware of their infection and as many as 30% who know they are infected are not receiving ongoing HIV care.
The affordability of medications for patients with complex diseases is a major issue as well. Treatment for HIV is expensive, with annual costs ranging from $23,000 to more than $50,000.17 Medication costs, which range from $11,262 to $25,000, account for much of the annual cost of care. A shortage of primary care clinicians in the United States that is projected to get worse also will affect whether people with HIV get appropriate treatment as they age. The specialists best trained for managing the care of older chronically ill patients are geriatricians. In the United States, reimbursement for primary care activities (including care of geriatric patients) is relatively low, leading to less interest in primary care as a career and thus exacerbating the shortage of qualified providers. At present, there are only 7,100 geriatricians in this country. If current trends continue, by 2030, when 36,000 will be needed, only 8,000 will be practicing.18 An estimated 50% of persons living with HIV/AIDS will be older than 50 years of age by 2015.19 This indicates that there will be a shift in the nature of HIV care, from a focus on the health concerns of younger persons to the needs of older people.
Because of the high cost of HIV care, outpatient focus, and poor reimbursement for primary care activities, many are concerned about the sustainability of HIV care in this country.20 In countries where access to cART remains low (some estimates are that only 10% to 25% of patients who need it are getting it), concern is greater. There is concern that even for patients now doing well on cART (such as the 3 million receiving cART through the U.S.-based PEPFAR program), it is uncertain whether funding will continue (the lowest cost cART is about $1/day per patient).21 Successful expanded management of HIV/AIDS throughout the world will require persistent political will, social action, and financial sacrifice.
How Can HIV Prevention Efforts Be Improved?
Despite all the progress that has been made in understanding and treating HIV, nearly 30 years into the AIDS epidemic, the rates of new HIV infections remain frustratingly high. Education and behavior change remain the first line of defense against HIV. Awareness about HIV still remains low in at-risk populations throughout the world, including the rural southern part of the United States. Behavior change can have a dramatic effect on HIV transmission as shown by the significant decline in new cases in MSM in the United States during the mid-1980s as concern about HIV/AIDS led to widespread adoption of safer sex practices. Condom use and provision of clean needles for IV drug users have proven effective at decreasing HIV transmission; yet cost and political/social obstacles have hindered widespread adoption.
Added to this is the effectiveness of cART at reducing the risk of sexual transmission to uninfected partners.22 Unfortunately, knowledge about the effectiveness of cART has resulted in a loss of the fear of AIDS and a tendency to engage in risky behaviors as a result. Those trends coupled with easier access to sex partners through the Internet and use of drugs such as Viagra, crack cocaine, and crystal methamphetamine have resulted in increased transmission of HIV in MSM populations throughout the world. Aggressive testing for HIV, treatment of those who are infected, plus educational efforts have the potential to significantly decrease new HIV infections in the future.23 Ultimately, this appears to be a cost-effective strategy, although practically speaking, it seems unlikely to be widely used.
Other strategies to prevent infection are works in progress. Development of a vaccine to prevent HIV has been thwarted by the diversity of HIV strains as well as the difficulty of ascertaining what constitutes protective immunity. Broadly protective antibodies, a hallmark of most vaccines, have been difficult to identify and develop, but there is renewed hope that effective approaches will be found. Pre-exposure chemoprophylaxis is being studied but hasn’t yet been proven to stop transmission.24 Microbicides, which could offer women the ability to exercise some control over their risk, are currently a high-priority area for research with promising animal data being translated to clinical studies in humans.
Can HIV Be Eradicated?
A number of properties of HIV enable the virus to establish persistent reservoirs of infection that evade the efforts of innate immune responses and are not susceptible to the effects of cART. Those properties include escape mutations that keep the virus ahead of immune response; integration of viral DNA into host cell genomes; establishment of a quiet latent infection in resting, long-lived, memory T-cells; and presence in areas of the body not easily accessible to drugs or immune response (ie, the central nervous system, genital tract, or mucousal surface of the gut).
For a time, realization of those viral properties led to a virtual cessation of efforts to find a cure for HIV infection. Recent research including work being done in Minnesota has provided new insight into the persistent nature of HIV that is pointing to potential approaches to eradicating it from the body. The recent case report from Berlin of a functional cure has further stimulated interest in developing new approaches to eradicating HIV.25 The NIH has resuscitated research funding for approaches that would flush HIV out of its hiding places and eventually lead to control of HIV infection without the need for indefinite cART (a functional cure).26
Conclusion
The questions raised in this article provide a window into the future of the HIV/AIDS epidemic and represent a roadmap for current and evolving research. Even as the success of the scientific quest to understand and treat HIV/AIDS is celebrated, new unexpected problems continue to develop. The very success of cART has led to an increased burden with more patients living with HIV than ever before (stressing available resources) and the phenomenon of disinhibition of behavior (as the fear of AIDS recedes with an overreliance on technology to solve any future problem). These issues and others will continue to challenge scientists, clinicians, and policymakers in the decades to come. Only hard work and judicious use of health care resources will guarantee that the next chapters of the HIV/AIDS story will have a positive ending. MM
Keith Henry is a staff physician with the HIV Program at Hennepin County Medical Center and a professor in the University of Minnesota’s department of medicine. Ogechika Alozie and Shulamith Bonham are fellows in the department of infectious disease and international medicine at the University of Minnesota.
Financial Disclosures for Keith Henry Research Support: Bristol-Myers-Squibb, Tibotec, GSK, Serono, Thera, and Pfizer, Centers for Disease Control, and NIH (NIAID). Speakers Bureau: Glaxo-Smith-Kline, Bristol-Myers-Squibb, Roche, and Gilead, Pfizer, and Tibotec. Honorarium: Glaxo-Smith-Kline, Bristol-Myers-Squibb, Roche, and Gilead, Pfizer, and Tibotec. Consultant: GSK, BMS, and Gilead. Stock Ownership: None
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