Since the first identification of AIDS in 1981, and the eventual discovery of HIV two years later, HIV/AIDS has become a dominant global public health priority with a wide range of humanitarian and economic implications.
According to the World Health Organization, nearly 70 million people have been infected with the HIV virus since the beginning of the epidemic, and approximately 35 million people have died of AIDS since the 1980’s. The Centers for Disease Control (CDC) estimates that there are approximately 1.3 million people in the United States who are infected with HIV.
While those statistics are alarming, it is important to acknowledge how far we have come in the fight against HIV/AIDS in the last three decades. “For those of us that have worked in HIV/AIDS over the past 20 years it’s almost impossible to imagine where we are now,” says Liza Solomon, MHS, DrPH, an HIV/AIDS public policy leader and a principal associate at Abt Associates. “Treatments were rudimentary and there seemed to be very little that medicine could offer.”
Since that time, new drugs have become available, medications have improved, side effects have lessened, and death rates have declined. Even more, AVERT, an international HIV and AIDS charity, estimates that in 2008 alone, over $15 billion dollars was spent on HIV and AIDS compared to $300 million dollars spent in 1996. This money from donor governments, low-income and middle-income country governments, the private sector, and individuals has helped fund research and treatments as well as fuel scientific advances in the fight against HIV/AIDS.
Scott Kim, MD, Medical Director for HIV Medicine at AltaMed Health Services, believes that new developments not only attest to the tremendous importance of government-funded basic science research, visionary pharmaceutical leaders, strong public advocates, and a federal government committed to extending care to all HIV-infected patients, but confirms that we have gone from a disease with a life expectancy that was barely a few years to a chronic disease with a long life expectancy.
Simply put, an HIV/AIDS diagnosis is no longer the automatic death sentence it was once considered.
“We can now speak of HIV/AIDS as a chronic disease, and for the first time, researchers and public health practitioners talk about an AIDS-free world,” Solomon says. “It is clearly not here now, but there is the sense that perhaps we can hope to achieve that within the foreseeable future.”
Research and Medications
Medications have changed significantly since combination antiretroviral drugs (ARVs) were first available in 1996. The development of ARVs—medications for the treatment of infection by retroviruses like HIV—has resulted in greater control of the disease and a prolonged, better quality of life for those infected.
Recent clinical studies have proved conclusively that individuals who are on effective antiretroviral treatments are significantly less likely to transmit HIV to an uninfected partner. The clinical trial called HPTN 052 (HIV Prevention Trials Network) showed a 96% reduction in transmission from an individual infected with HIV to their uninfected partner.
JoAnn D. Kuruc, MSN, RN, a program manager in the AIDS Clinical Trials Unit at the University of North Carolina at Chapel Hill, believes research related to HIV and treatments for the disease is responsible for the great strides achieved in the development of medications over the last 30 years.
In the past, HIV drug treatments consisted of a large number of pills taken at multiple points throughout a day. “Not only was it challenging to remember to take the pills, but the sheer volume that you had to swallow was an obstacle to overcome,” says Kuruc.
Additionally, side effects (nausea, vomiting, and diarrhea) associated with early medications were themselves a barrier to adherence and compliance. Kim says toxicities associated with frequent dosing included lipodystrophy, kidney stones, hepatic inflammation, diarrhea, and nausea.
Today, treatments have improved greatly, resulting in minimal side effects and requiring fewer pills—and in some cases—just one pill per day.
“Research in the drug development has led to more options, allowing individuals with severe side effects or drug resistance to switch to different medication regimens,” Kuruc says. “Years ago, there was only one class of drug available to treat a person with HIV infection, but now this has increased to five different mechanisms or classes of drugs.”
Kali Lindsey, Director of Legislative and Public Affairs at National Minority AIDS Council, reports a swarm of new biomedical interventions resulting from investment in research—including scientific advances such as treatment as prevention and pre-exposure prophylaxis—that have provided exciting new tools to combat the spread of HIV.
The CDC defines pre-exposure prophylaxis, or PrEP, as a new HIV prevention method in which people who do not have HIV infection take a pill daily to reduce their risk of becoming infected.
“Pre-exposure prophylaxis is the use of an antiretroviral drug in HIV-negative individuals who engage in behaviors that place them at heightened risk for acquiring HIV,” says Amesh Adalja, MD, FACP, an infectious diseases physician at the University of Pittsburgh Medical Center. “By taking anti-HIV medications prior to exposure, they substantially decrease the risk of acquiring HIV if they are exposed.”
The pill contains medicines that prevent HIV from making a new virus as it enters the body and helps keep the virus from establishing a permanent infection. If used effectively and by persons at high risk, PrEP has been shown to reduce the risk of HIV infection.
According to the CDC, in July 2011, researchers announced the results of the TDF2 study that found a once-daily tablet containing tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) reduced the risk of acquiring HIV infection by roughly 62% overall in the study population of uninfected, heterosexual men and women. The Partners PrEP study also found that daily doses of TDF/FTC or daily doses of tenofovir alone reduced HIV transmission among heterosexual serodiscordant couples (in which one partner is infected with HIV and the other is not) by 73% and 62%, respectively.
CDC is also evaluating PrEP’s effectiveness in preventing HIV infection among individuals exposed to HIV through injecting drugs, but those results are not yet available.
Eradicating HIV Reservoirs
While drug treatment has not provided an actual cure, research is now honing in on ways to eradicate the remaining reservoirs of HIV from infected individuals whose HIV is fully suppressed by therapy. Research focused on eradication is still in the early phases and much of the analysis and data to date has been obtained from ex vivo studies, as well as a few Phase I clinical trials, Kuruc explains.
Highly active antiretroviral therapy (HAART) is capable of suppressing HIV viral replication in the body; however, it is incapable of eradicating the virus. When HAART is stopped, viral replication reemerges. The viral rebound stems from virus that exists in latent reservoirs. There may be distinct sites throughout the body that function as “latent cell reservoirs,” perhaps in the lymphoid tissue, the gastrointestinal tract, or the central nervous system. Virus is also known to persist in CD4 cells (T cells) that are in the resting, or quiescent state, found either in the blood or in tissue.
“One of the first steps in developing a cure involves the identification, activation, and elimination of the resting CD4 cells from the reservoir and getting the virus released,” Kuruc says. “Once expressed from the cells, the patient’s current HAART would inhibit new infection from occurring.”
Kuruc adds that scientists are looking at various ways to express the virus from the latently infected cells. Stimulating key areas of the cell that are known to play integral parts in HIV storage (chromatin) or transcription (P-TEFb, or the NF-kB proteins) have been the focus of much of this research.
One approach proposed to stimulate HIV-1 expression is the use of a histone deacetylase (HDAC) inhibitor. Suberoylanilide hydroxamic acid (SAHA), or Vorinostat, is one HDAC inhibitor that is getting much attention in this field. In 2006, Vorinostat was approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. A recent ex vivo study confirmed the ability of the drug to disrupt latently infected cells. David Margolis at UNC, in a proof of concept study, demonstrated significant increase in the expression of viral RNA when SAHA was given in a clinical trial.
“Although this was an enormous breakthrough, research still needs to determine: if the reservoirs are depleted; if the cells die after releasing the virus; and if the drug is safe to take for an extended period of time without any adverse effects,” Kuruc says.
Kuruc explains that once the virus is released by the latent cell, eradication of the virus and obliteration of the cells remain a concern. Recent ex vivo research illustrated that viral expression from the latent cell may not lead to cell death. Thus, it may be necessary to combine the activation and expression of the virus from the latent cell (SAHA) with other therapies.
“Few scientific and medical challenges are as daunting and complex as the attempts to develop a cure for HIV infection,” says Kuruc. “The progress made so far in understanding the complex biology of HIV infection and the stunning achievements of HAART should give us hope that we can overcome the recognized and the yet-to-be-discovered challenges of persistent, latent HIV infection.”
Vaccines will lead the upcoming fight against HIV, says Robert McNally, PhD, President and CEO of GeoVax, a biotechnology company developing human vaccines for diseases caused by HIV and AIDS.
So far the results have been encouraging. In 2009, Sanofi Pasteur, the vaccines division of Sanofi-Aventis, participated in a preventive vaccine trial that lowered the rate of HIV infection by 31.2%. The trial, involving more than 16,000 adult volunteers in Thailand, demonstrated that an investigational HIV vaccine regimen was safe and modestly effective in preventing HIV infection.
“Albeit modest, the reduction of risk of HIV infection is statistically significant. This is the first concrete evidence, since the discovery of the virus in 1983, that a vaccine against HIV is eventually feasible,” says Michel DeWilde, R&D Senior Vice President for Sanofi Pasteur, in a 2009 press release.
McNally says GeoVax is also at the forefront of this effort, with a substantial scientific lead for an effective preventive vaccine, thanks to the door opened by the Sanofi Pasteur trial. “This glimmer of hope for an effective vaccine has paved the way for biotech companies like GeoVax to gain traction with the next generation of products.”
Currently, McNally reports that human clinical trials for the preventive use of the GeoVax HIV/AIDS vaccine found that their vaccines were well tolerated with no or mild, local and systemic reactions in the majority of trial participants and that 80% of both low and full dose trial participants responded to the vaccine, which stimulated anti-HIV T cells (white blood cells) and antibody responses.
“The goal is to produce a vaccine like the one for polio where large portions of the at-risk population could be vaccinated; thus, over time, the incidence of HIV will decline to the point where the vaccine will hopefully become unnecessary,” he says.
Decades ago, HIV testing initially consisted of a series of blood tests that took several weeks for the results. Now HIV testing has become easier and more accessible with rapid testing where the test results are available within 45 minutes.
“Newer blood testing techniques currently being marketed not only allows for quicker turnaround of test results but is sensitive enough to detect HIV prior to the body developing antibodies to the virus, thus having persons diagnosed in the earliest stages of the disease (known as the acute phase); [and] therefore, allowing individuals to be diagnosed and treated prior to the virus doing severe damage to the immune system,” says Kuruc.
Solomon says that researchers at Abt Associates are working on two different projects with the goal of educating individuals about HIV, making HIV testing available, and linking individuals into care. The first project involves working with minority serving institutions (colleges or universities that serve predominantly minority students) to develop HIV prevention programs for their students.
“The nursing school at Florida International University’s program is designed to train nursing students to be peer educators and provide HIV prevention education while at school,” Solomon says. “The students are a resource to their peers while they are students, and will develop skills regarding HIV testing and prevention that they will utilize in their future role as practicing nurses.”
Abt Associates’ other HIV project involves a large effort to provide HIV testing to minority men who have sex with men and do not know their HIV serostatus. The goal is to identify 3,000 previously undiagnosed HIV positive men and link them into care.
“We are working with community-based organizations and academic institutions throughout the country to implement this three-year testing and linkage program. A critical component of this program is to bring HIV testing to non-traditional settings so that individuals who may not routinely interact with the medical care system have access to testing,” says Solomon.
Patient Protection and Affordable Care Act
While the developments in biomedical research over the last few years has been exciting to witness, nothing is as critical to the fight against the HIV/AIDS epidemic than the passage and now implementation of the Patient Protection and Affordable Care Act (ACA), according to Lindsey.
“The single largest barrier to HIV/AIDS services in this country, whether prevention or care, is lack of access to quality, affordable health care,” says Lindsey. “While not perfect, the ACA will go far to providing such access, both through its insurance exchanges and its Medicaid expansion. Its patient’s bill of rights will also help ensure that people living with HIV or AIDS cannot be discriminated against by insurance companies through rescission or denial of coverage based on preexisting conditions.”
Currently, only about 13% of people living with HIV/AIDS have access to private insurance. What’s more, less than 30% have achieved viral suppression through adherence to a treatment regimen. Another 20% of people living with HIV are not even aware that they carry the virus. Minorities not only have higher rates of infection, but also suffer significantly poorer health outcomes, including increased mortality.
With more than 56,000 new HIV infections in the United States each year, the AIDS epidemic is far from over. And despite better treatments, there is still no cure. Lindsey believes that expanding access to health care is the single most important thing our nation can do to both improve health outcomes for those living with HIV/AIDS while also working to bring an end to the epidemic itself.
“For the first time in over thirty years, it is possible to realistically envision an end to HIV/AIDS. But ending this epidemic will not be easy. It will require bold, visionary leadership and the commitment of all of us to successfully translate the promise of this moment into a world without HIV/AIDS. Science and research have given us powerful tools; now we must decide to act.” MN