To Be Continued: The Search for a Cure for HIV

Effective treatment has helped curb the epidemic, but practical cures have been elusive, notwithstanding last month’s news about a bone-marrow transplant.

Thomas Reinke
Contributing Editor

It has been a disaster for humanity around the world, but there’s no denying that the human immuno­deficiency virus is an absolutely brilliant micro­organism when it comes to its own survival. As a virus, it normally would be fended off by the immune system. Somehow, though, HIV prevails over the immune system from the outset by infecting the very cells that are meant to trigger the immune system’s defense. The affected cells are CD4 T cells, a category of white blood cells. Once HIV establishes a foothold in those CD4 cells, it is able to replicate itself in other CD4 cells. The result is that HIV wears down the immune system by reducing the count of functioning CD4 cells.

HIV’s smarts don’t stop there. Somehow, the virus seems to have anticipated that scientists would be coming after it, so it developed the capability to morph itself into two forms: an active form that spreads infection and may lead to a diminished immune system and full-blown AIDS, and a latent form that hangs out in a reservoir of infected CD4 cells that hide from today’s medications and exist for decades.

Last month, the world heard about a second person, the “London patient,” being cured of HIV infection with a bone-marrow transplant. It’s an exciting development that may open up new avenues of research. But bone-marrow transplants are arduous for patients, carry all sorts of risks, and are expensive. Aside, perhaps, for HIV patients who are also being treated for cancer—the London patient had Hodgkin’s lymphoma—they are not even remotely practical.

That leaves the current cohort of HIV treatment medications, which don’t get the credit they deserve for turning the tide against a global epidemic. In more good news, ViiV Healthcare reported positive results last month for an HIV combination treatment that would be administered as a monthly injection instead of daily pills. Some important cautions: The research was paid for by ViiV, an offshoot of GlaxoSmithKline and Pfizer, and company-sponsored research always needs to be considered with care. Regulators in the United States and Europe haven’t approved the combination yet. If they do, price and affordability are likely to rear up as issues.

Two types of cure

Still, as successful as they have been and as promising as the monthly injections might be, the current cohort of HIV treatment medications do a good job of suppressing the virus, but they have no impact on the latent reservoir. If cure means no longer needing to treat, then they are far from a cure for HIV, and the dormant virus reasserts itself if the medications are stopped.

So, notwithstanding the bone-marrow transplants, the search for a true cure to HIV is far from over. Robert Siliciano, MD, a researcher at Johns Hopkins, says one approach is a “sterilizing cure” that eradicates HIV from the body. The other approach is a “functional cure” that effectively reduces the viral load so it cannot be transmitted or progress to AIDS.

The search for a sterilizing cure is attempting to eliminate the reservoir of latent HIV cells. The research so far has not found a way to directly eliminate the resting HIV cells, so the strategy is to shock the dormant infected cells into an active state and then kill them with existing antiretroviral medications. According to Siliciano, several small-molecule drug candidates have worked in vitro but failed in vivo. The latent HIV cells have been very protective of their secrets for hiding and long-term survival.

Currently, it is extremely difficult to flush latent infected cells out of their latency. So far, this strategy—which has been dubbed “shock and kill”—relies on a class of drugs called HDAC inhibitors that come with severe adverse effects.

Gene editing is another strategy that could conceivably be used to cure HIV. For example, researchers have had some very preliminary success with using the CRISPR technique to remove HIV genes from infected cells.

The idea of a functional cure is a practical solution that reflects the difficulty in finding a sterilizing cure. The current arsenal of three- and four-drug combination pills suppress HIV to undetectable levels, thus stopping the progression of HIV to AIDS and the transmission of HIV to others.

During 2016 and 2017, half of new HIV diagnoses were concentrated in 48 “hotspot” counties, primarily in Southern states, plus Washington, D.C., and Puerto Rico.

The central approach to a functional cure is to find a medication therapy regimen that, over time, will allow therapy to be totally discontinued. Two studies in Europe have shown that when antiretroviral therapy is started very early on, a small portion of study subjects went several years before the virus re-emerged.

Containment strategy

In the absence of a cure, HIV remains a social and public health challenge in the United States and worldwide. As of 2017, there were an estimated 1.1 million people in the United States living with HIV, including about an estimated 160,000 people who have not been diagnosed. Between 2010 and 2013, the number of new HIV cases fell slightly from 42,000 to about 39,000 annually. Since then the annual number has remained stable even though federal expenditures for HIV and AIDS run about $20 billion annually.

During 2016 and 2017, half of new HIV diagnoses were concentrated in 48 “hotspot” counties, primarily in Southern states, plus Washington, D.C., and Puerto Rico.

The stigma surrounding HIV plays a large role in limiting diagnosis and treatment in the South and rural areas.

Two challenging statistics in terms of prevention and treatment are that approximately 23% of new infections are transmitted by individuals who are unaware of their infection, and approximately 69% of new infections are transmitted by those who know they have HIV but who are not taking medications. The CDC estimates that only 51% of individuals maintain suppression through a consistent adherence to their medications.

The transmission of HIV is also tied to the opioid crisis; 2015 marked the first year in two decades that the number of HIV cases attributed to drug injection increased.

The Trump administration’s program to stop new HIV infections (see “In Trump, HIV/AIDS Groups Find an Ally Who’s Tough To Love”) relies on scaling up and being more successful with the core methods for combating HIV, such as diagnosing cases as early as possible after infection, encouraging adherence to achieve sustained viral suspension, and limiting transmission in at-risk populations.

A coordinated worldwide effort is paying off in containing the spread of the disease. In 2010, only 7 million (21%) of the 33 million people infected with HIV worldwide were on antiretroviral therapy. Deaths from AIDS were running at 1.8 million per year. One priority was providing access to medications in low- and middle-income countries. The annual cost of medications was $160 per person.

Several years ago, the United Nations kicked off the UNAIDS 90-90-90 program with goals to diagnose 90% of all HIV-positive people, provide antiretroviral therapy (ART) to 90% of those diagnosed, and achieve viral suppression for 90% of those treated, all by 2020.

Those percentages mean that 81% of all HIV-positive people will be on medications and 73% of all HIV-positive people will be out of danger for AIDS and for transmitting the disease.

By the end of 2017 things had changed dramatically. The global number of people on ART reached 21 million, or 57% of the 37 million infected population, and AIDS deaths dropped to less than 1 million people per year—still an enormous number but notable progress, especially when set against earlier projections that showed the death toll increasing. Medications were being upgraded in many countries to more effective and tolerable regimens.

Much of the progress was tied to the fact that the median price of first-line regimens was down to $85 per year. Never underestimate price as a factor in the efficacy of a health care intervention.