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Over the past 20 years, the treatment of patients with HIV-related neurologic complications has evolved and improved. Among changes, clinicians are treating HIV earlier and more aggressively, rather than waiting for patients to show signs of advanced immunosuppression, and antiretroviral therapies have become less toxic.

Less-toxic, more effective medications, and a change in the timing of treatment have led to improvements in the care of patients with HIV and AIDS and the neurologic complications that can accompany them.

Roughly 40 years have passed since HIV began sweeping across the world, and the virus is no longer the death sentence it once was, in part because of key medical developments over the last two decades. That includes a shift to treating patients with HIV immediately rather than waiting for them to show signs of advanced immunosuppression, as had been standard practice for years.

“It's remarkable to folks these days that in the earlier days of the epidemic we recommended not using our HIV therapies until the immune system had become compromised to some degree,” said David Clifford, MD, FAAN, the Melba and Forest Seay Professor of Clinical Neuropharmacology at Washington University in St. Louis.

HIV enters the nervous system within two weeks of a person's primary infection, said Deanna Saylor, MD, MHS, associate professor of neurology and a neuro-infectious disease and neuroimmunology specialist at Johns Hopkins Hospital. Many proteins the virus produces during replication are toxic to neurons, microglia, and other cells in both the brain and peripheral nerves, which she said can lead to the subsequent development of neuropathy and cognitive impairment.

Delayed treatment therefore allows patients' CD4 cell counts to drop and further exposes their brains to circulating virus, Dr. Clifford said, which “results in both potentially direct damage in the brain from the inflammation that the activated cells generate in the brain.” That delayed treatment leaves an opening for viral growth in the brain that can evolve independently in cells there, he added.

People with HIV who are not well-treated today resemble what the medical community encountered in patients early in the epidemic, said Jessica Robinson-Papp, MD, MS, FAAN, a neurologist and professor of neurology at Icahn School of Medicine at Mount Sinai in New York City.

Forty years ago, doctors saw high rates of central nervous system opportunistic infections as well as higher rates of significant neuro-cognitive impairments and peripheral neuropathies—both of which “are caused by direct effects of HIV itself, especially when advanced immunosuppression is present,” Dr. Saylor said.

As the immune system becomes compromised in untreated HIV, patients may develop toxoplasmic encephalitis, a condition that housecats can carry and which can cause large abscesses in the brain. Active, independent brain infection tends to be a later-stage condition that arises when the immune system has further eroded. Patients also may develop fungal infections, tuberculous meningitis, staphylococcal meningitis, and neurosyphilis.

“Syphilis can be a latent infection, and in the setting of HIV [it] can involve the brain earlier and more aggressively,” Dr. Clifford said.

Doctors have known about most neurologic complications of HIV and AIDS for a long time, Dr. Clifford said, but there have been isolated cases of a “very rare phenomenon”—cerebrospinal fluid escape—in which “the virus is present in the spinal fluid and presumably in the brain but is undetectable in the blood.”

“We didn't know about cases like that,” he said. “They are rare cases, but it's a real phenomenon that neurologists have to be aware of—that the virus can escape in the brain compartment and not be active in the blood.”

Viral escape can trigger neurologic complaints such as headaches, a new encephalopathy, or motor dysfunction, Dr. Clifford said. Clinicians should consider that viral escapes have happened if new neurological complaints develop without obvious cause, he added, “even when the serum viral load is undetectable.”

Transition To Immediate Treatment

Neurologists who spoke to Neurology Today offered differing opinions about when the shift to immediate treatment of patients with HIV occurred, but they agreed it happened at least within the last 15 years.

Doctors initially delayed treatment in part because they feared losing a specific therapy because of the evolution of HIV—a retrovirus that mutates at high rates and can develop drug resistance—and because of toxicity concerns, Dr. Clifford said.

“It's striking that we didn't come to that conclusion a lot earlier than we did, really,” Dr. Clifford said. “But the therapies were pretty toxic, and we had this long experience when we used monotherapies or serial therapies without really high potency that we would lose drugs to the development of resistance.”

Drugs used 20 years ago also required consistent use, according to Dr. Clifford. If patients didn't take them as prescribed, the medications soon became ineffective. (Today's drug therapies still require consistent use, he added, but they “are more forgiving because they in general are more potent and have longer half-lives.”) First-generation anti-retroviral therapies (ART) were associated with “significantly higher risk of neurotoxicity” than today's drugs, and the longer patients were exposed to them, the more likely they were to develop those toxicities, Dr. Saylor explained. Early ART caused neurologic side effects, such as severe and painful peripheral neuropathy, she said, and were implicated in causing significant cognitive impairment and myopathy.

Modern medications still have side effects and toxicities, but they occur less frequently, said Dr. Saylor, who noted some of the newest classes of medications are integrase strand transfer inhibitors like dolutegravir and post-attachment inhibitors like ibalizumab-uiyk. Today's drugs are less toxic, have much lower rates of resistance, and are more effective, she added.

As therapies have become safer, Dr. Clifford said, “there really is no barrier to starting them immediately.”

“Drugs in the later years have become more potent and less prone to resistance generation,” he said. “It's unusual these days to have any patient that has truly resistant virus that we can't put together an effective therapy to treat.”

For some time, Dr. Clifford said, doctors questioned whether several of the drugs they used to treat HIV did not enter patients' brain compartments.

“The blood-brain barrier is a barrier of many things, including the entry of drugs that are very protein-bound,” Dr. Clifford said, adding, “It's turned out that's not been as large a problem as we feared, but we did worry quite a lot about that.”

Today, people are more aware of HIV and testing is more widely available, so infections are picked up earlier. Neuropsychological testing for people with HIV/AIDS now goes beyond a basic screening, offering a more in-depth evaluation of conditions such as depression, cognitive changes, and developmental learning disorders, said Ronald Ellis, MD, PhD, FAAN, a professor of neurosciences at UC San Diego Health who specializes in the diagnosis and treatment for adults with HIV/AIDS.

“The milder forms of cognitive impairment are one of the most common diagnoses or referring problems in my clinic,” Dr. Ellis said. “People with memory and attention problems, typically in their 60s and 70s, come in and ask, ‘Do I have Alzheimer's disease?’ And it isn't always clear right off the bat. But the Alzheimer's disease diagnostic tests are sufficiently sensitive and specific. I wasn't confident two or three years ago that we could really pin it down to ‘This person has Alzheimer's disease.’”

Treatments, meanwhile, are more widely available than they used to be, according to Dr. Saylor. This makes it possible for doctors to prescribe them to all patients regardless of their level of immunosuppression.

Modern ART has simplified HIV treatment, too, according to Dr. Robinson-Papp. Many patients now take combination pills once a day, she said, while longer-acting injectable medications are another option and given once a month.

“I personally don't have a lot of people on those yet, but they are out there,” Dr. Robinson-Papp said.

Doctors told Neurology Today that these longer-term treatment options can benefit people who find a regular regimen of taking medicine challenging—for different reasons, including substance abuse, certain personality traits, or psychiatric conditions.

“The requirements for personal responsibility for compliance can be reduced for folks that really have a hard time with compliance for a variety of reasons,” Dr. Clifford said. “And so we do have emerging options that again allow full control of the virus even in people that are challenged.”

Currently, as treatment starts earlier and with more effective drugs, the most common neurologic complication of HIV is mild neurocognitive syndrome, which Dr. Clifford said “results in people not performing quite at their expected levels but not seriously impaired.”

“The opportunistic complications are much rarer these days than they were in the early days of the epidemic because most of them are quite tightly linked to immunodeficiency,” he said.

Dr. Ellis called the advances in treatment for the virus and its neurologic complications “just incredibly tremendous.” “I trained in an era when people used to come into the hospital and die routinely [from] just horrible, horrible opportunistic diseases,” he said. “So now ... there's plenty of data showing their lives are not normal, but they're a lot better than they used to be.”

As medications advanced, the type of care given to HIV patients changed, too. Without effective treatments for what had been a fatal disease, health care professionals and caregivers focused more on palliative care. They managed patients' pain and other symptoms within “the framework of someone who you don't expect to live very long, and that's a very different approach to managing chronic pain in someone who has a normal or near-normal life expectancy,” Dr. Robinson-Papp said.

“Palliative [care aims] ... to make them as comfortable as possible with the idea that their function is probably not going to be 100 percent, but what you want is comfort,” she said. “And then [with] someone who is not in that situation, your goal is really supporting function over the long-term. The approach to that is very different, and I think one big difference in the last 20 years is how we think about opioid treatment of patients, and that's always changing.”

HIV and AIDS emerged during the days of the so-called “war on drugs,” Dr. Robinson-Papp noted, and so people took a more conservative approach toward prescribing medications like opioids. But that shifted in the late '90s and 2000s when use of the drugs became more liberal. Opioid use has been fairly common in the HIV community, she said, but over the last decade, the pendulum swung the other direction.

She believes most people would agree that doctors should try to avoid prescribing opioids for patients with chronic pain who do not already take them because the risk of developing opioid use disorder is too high. Patients who have been taking opioids, however, may have passed the period of high risk of developing an addiction. They may be physically dependent on the medication—not addicted—and doctors may risk “rocking the boat in an otherwise stable patient” by taking them off opioids, Dr. Robinson-Papp noted.

Patients with HIV and AIDS tend to have many comorbidities, including neurologic conditions such as neuropathy and migraine, Dr. Ellis said.

“The typical patient who comes into my clinic will be on 20 different medications, and most of them aren't actually to treat HIV but to treat their diabetes, high blood pressure, you name it,” he said. “So they're not healthy persons. Their life span is extended, but their health span is not good.”

Some patients benefit from drugs used to treat Alzheimer's disease symptomatically, such as donepezil (Aricept), which Dr. Ellis said is commonly prescribed.

Medications such as Ritalin and Adderall also help some people, as it can give a boost to people with mild learning disabilities, he said.

The Legacy Effect

Doctors now appreciate that an individual's nadir CD4 count—the lowest CD4 count they have ever had in the course of their HIV infection—can have long-lasting effects on patient outcomes, Dr. Saylor said. They now know that patients with lower nadir CD4 counts have higher rates of cognitive impairment, even many years after their nadir occurred and many years after their CD4 counts have normalized.

That result—dubbed “the legacy effect”—is “a consequence of long-term chronic HIV infection, where neuronal damage which was triggered prior to the initiation of [combination antiretroviral therapy] may not be fully reversible,” according to a study published in the September 2018 edition of the British Medical Bulletin.

“We now know that the greatest degree of immune suppression that someone has had at any point in their HIV infection is correlated with a variety of poor outcomes, including non-neurologic [sequelae], like heart disease,” Dr. Saylor said.

People have been living longer with well-controlled disease, she said, but ongoing systemic inflammation that results from a viral infection like HIV has multiple negative health consequences.

“The [ART] does not quite normalize levels of chronic systemic inflammation,” Dr. Saylor said, “and so, over time, those chronic, albeit low, levels of ongoing inflammation lead to higher rates of disorders we associate with older age—heart disease, chronic kidney disease, and for neurology, earlier onset of non-HIV-related dementias as well as early onset of stroke.”

Dr. Saylor estimated that these conditions occur about a decade earlier in patients with HIV than they do in people without the condition.

“I think there's a lot of great research happening right now in the field of HIV-related stroke. For example, researchers are investigating whether we need different primary and secondary stroke prevention strategies for people with HIV than the general population,” she said, noting that HIV likely at least doubles the risk of a person experiencing stroke. “The mechanisms that cause stroke are different in people with HIV. ... Seeing where that goes in the next few years will be interesting.”

People who are immunocompromised also have an increased risk of cancer, particularly central nervous system lymphomas caused by the Epstein-Barr virus, Dr. Robinson-Papp said. Her own research has shown that dysfunction in the autonomic nervous system of people living with HIV contributes to increased morbidity and mortality. Associations have been found between autonomic fibers dysfunction and heart arrhythmias; autonomic dysfunction and chronic kidney disease; and end-stage renal disease and chronic liver disease and peripheral neuropathy, according to her research.

“Autonomic neuropathy is an under-the-radar problem ... [and] not something that people usually complain of or is obvious,” Dr. Robinson-Papp said. “Pain is quite the other way. It's extraordinarily common in people with HIV.”

To date, studies have not shown that the new ART therapies reverse HIV-associated neuro-cognitive impairment, but Dr. Saylor said she expects to see lower rates of such impairment in the years to come.

“I believe HIV-associated neuro-cognitive impairment will become less and less of an issue,” she said. “With everyone being started on ART at the time of their HIV diagnosis, more and more people with HIV will have never experienced advanced immune suppression, drastically reducing their risk of future HIV-associated cognitive impairment.”

Dr. Saylor identified major risk factors for neuro-cognitive impairment in HIV as current advanced immunosuppression or a prior history of advanced immunosuppression. But earlier, more aggressive treatment could prevent those issues from occurring.

“With new strategies of beginning ART as soon as someone is diagnosed with HIV, more and more people are initiating ART before they ever develop immunosuppression, thus dramatically reducing their future risk of neuro-cognitive impairment from HIV infection,” she said.

Dr. Saylor, who spends most of the year in Zambia, also emphasized her hope that HIV researchers will focus their studies on the people who could benefit from it the most.

“A lot of the research around HIV has been conducted in the US and other high-income settings, but we know that 70 percent of people with HIV live in sub-Saharan Africa, and they have different risk factors for neurological disease than populations in Western countries,” she said, noting residents there also have different genetic susceptibilities, environmental exposures, medical comorbidities, and socioeconomic conditions than other parts of the world. “It's important that we continue to push for high-quality research in the region that has the greatest number of people impacted by this infection.”

Aging With HIV

Thanks to the advances that have occurred in recent years, people are living longer with well-controlled HIV, and many institutions have shut down their dedicated HIV inpatient services because they no longer see high rates of advanced infections. At the same time, doctors now face a new frontier—the intersection of HIV and aging.

Many patients with HIV are in their 40s, 50s, and 60s but not many have reached their 80s, Dr. Robinson-Papp said, partly because many patients with HIV and AIDS did not survive the early days of the epidemic, but also because acquiring HIV later in life is not as common. And questions surround how the virus will interact with conditions seen in older people, such as Alzheimer's disease, Parkinson's disease, and dementia.

“There's a lot of interest in the research community as a whole and also in the patient advocacy community about aging right now,” Dr. Robinson-Papp said, adding, “HIV is undoubtedly in the brain and leads to cognitive impairment. Will they be at increased risk?”

Living a healthier lifestyle in general—from remaining active physically and mentally to not smoking—can keep the brain and vascular system healthy so patients with HIV can approach their condition from a better place.

“There's been a change to evolve toward healthy lifestyles, and the care of general medical comorbidities are very important to optimize health,” Dr. Clifford said.

Having lived through the early days of the HIV/AIDS epidemic when people who developed neurologic complications faced a grim prognosis, Dr. Clifford said, he has seen how the introduction of truly effective, tolerant therapies “has just transformed life for a large number of people.” He called it “really one of the exciting achievements of medicine.”

“The bottom line is people are being treated earlier and more effectively,” Dr. Clifford said, “and fewer people have immunodeficiency to result in complications.”