Pharmacovigilance and Post-Marketing Trials: Stavudine’s Last Fight – Part I

29th June 2018 (Last Updated August 8th, 2019 10:43)

In a three-part special, Guillaume Trusz, Antonia Wadley & Peter Kamerman, discuss the reasons behind recent post-marketing clinical trials for the HIV antiretroviral stavudine

Pharmacovigilance and Post-Marketing Trials: Stavudine’s Last Fight – Part I

Beyond testing to see if a new drug carries out its intended function, one of the primary goals of running clinical trials is to determine the adverse effects of the drug. These effects can range from minor impairments, such as headaches or coughs, to more long-term and detrimental ones, such as various forms of cancer. Pharmacovigilance, or the process of actively looking for the adverse events, can have a significant impact on how drugs are marketed and prescribed to patients. It is the responsibility of the clinical operations industry to ensure that those adverse effects are accurately reported and properly communicated.

More often than not, adverse effects are temporary and are fully eliminated once a patient has stopped taking the current medication and has transitioned to another treatment. But what if that was not the case, and simply stopping the problem treatment was not a straightforward option?

The HIV Impact

Nowhere in the world is the impact of the human immunodeficiency virus (HIV) bigger than in Southern Africa. In terms of HIV prevalence, Swaziland, Botswana, and Lesotho dominate the list, but in terms of total number of patients, South Africa leads by a wide margin. Within a population of roughly 55 million, it is estimated that more than 7 million people are living with HIV. This means that around 13 percent of the South African population lives with the virus.

To put these data in perspective, out of a population of more than 300 million in the U.S., roughly 1 million people are living with HIV, or 0.33 percent of the population. South Africa currently has over one-fifth of the world’s HIV positive population, and it is estimated that over 3.5 million South Africans (HIV patients) are on some form of antiretroviral (ARV) medication; by far the largest such treatment program in the world.

HIV Cure Remains Elusive

HIV causes a progressive failure of the host's immune system, more specifically the host's cell-mediated immune system, which can lead to various opportunistic infections such as tuberculosis, hepatitis, or even cancers such as Kaposi's sarcoma and non-Hodgkin's lymphoma. A cure for HIV infection remains elusive.

One of the main issues with finding a cure is that reverse transcription (the process through which the virus replicates after it has infected a host cell) is an extremely error prone process. While one may think this would be a problem for the proliferation of the virus, it is more of a problem for developing treatments that are able to target specific molecular components of the virus’ lifecycle. As a result, it is currently impossible to be cured of HIV, and instead, treatments merely serve to hold back the virus by delaying its replication.

The first drug to receive Food and Drug Administration (FDA) approval for the treatment of HIV was GlaxoSmithKline's zidovudine (better known as AZT) in 1987. Several other drugs, which interfered with the viral reverse transcription process, followed. These drugs are often referred to as the "d-drugs," and include Bristol-Myers Squibb's stavudine (or d4t). All these early drugs had significant adverse effects, which could limit their use, but in those early years of HIV drug development, when death rates were drastically high, clinicians and researchers were more concerned with getting a viable drug product to patients and as quickly as possible. However, HIV treatments have dramatically evolved, and now target more than the reverse transcription process (e.g. blocking the virus entry into the cells and the incorporation of the viral genome into ours), and they have fewer and less severe side effects than did the early drugs.

Moreover, we have learned that by using combinations of drugs (whether new or old), the ability of the virus to escape the effects of the drugs is limited. Combination therapy has now become the norm, and routine drug combinations are frequently manufactured as a single pill. Such advancements have helped transform AIDS from a progressive terminal illness to a manageable chronic disease. Nowadays infected individuals can have an almost normal life expectancy. Yet, in spite of that, what happens when people are neither able to afford nor have access to these state of the art treatments? Older treatments may be able to control the virus, but this benefit may come with significant adverse effects that impact the patient’s quality of life.

Stavudine – Africa's First Generic ARV

In 2003, in order to expand access to affordable treatments for HIV/AIDS throughout sub-Saharan Africa, Aspen Pharmacare (one of the biggest generics companies in the world, and currently the largest drug company in Africa) was granted licenses from the companies that developed the drugs to create generic versions of some of the early ARVs. That same year, Aspen Stavudine was launched and it became Africa's first generic ARV. Since then, stavudine has become the most widely used antiretroviral drug as part of the combination therapy for treating HIV infection in low-income countries.

Stavudine belongs to a class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), and acts as a nucleoside analog of thymidine. When the HIV attempts replication within a host's cells, stavudine will incorporate itself within the newly formed strand of viral DNA, essentially causing termination of the DNA elongation. By doing so, the drug prevents the virus from further propagating. Stavudine is often taken with a combination of other HIV drugs, and this triple combination of drugs is called highly active antiretroviral therapy (HAART).

Managing Adverse Effects

Neuropathy, or nerve damage, has emerged as a common complication and direct consequence of HIV infection. Distal sensory polyneuropathy leads to pain, numbness, and tingling in the patient’s hands and feet. However, treating the viral infection that underpins the neuropathy is not always a solution to the problem because some treatments, particularly stavudine, are themselves neurotoxic and are associated with the development of a toxic neuropathy, which is phenotypically very similar to distal sensory polyneuropathy. The combination of the drug’s high neuronal toxicity, and the large number of people (especially in low- and middle-income countries) on stavudine, means that toxic neuropathy is the most predominant cause of neuropathy among HIV patients. Moreover, neuropathy isn’t the only major adverse effect of stavudine, it is known to cause problems with fat metabolism (lipodystrophy), lactic acidosis (potentially fatal), liver damage (hepatomegaly and hepatotoxicity), as well as pancreatitis.

So, here is a life-saving drug that is quite commonly associated with major adverse effects that directly affect quality of life, and even worse, whose adverse effects have the potential to compromise treatment adherence in patients. This would not only cause harm to the patient (dramatically reducing their life expectancy), but treatment noncompliance would mean rapid disease progression, potential viral resistance, and an increase in the risk of transmitting the virus to someone else.

Compared to other HIV medication, stavudine's price tag is relatively low, and due to the sheer number of HIV cases in Southern Africa, it is of no surprise the drug has remained in use for so long in the front-line treatments. But how do we deal with such adverse effects long after a drug has been put on the market, and how do we manage the drug considering that alternative treatments are not a simple option?

 

Guillaume Trusz

Antonia Wadley

Peter Kamerman

 

Brain Function Research Group (BFRG), University of the Witwatersrand

 

References:

United Nations International Children’s Fund (UNICEF): HIV and AIDS Overview. (https://www.unicef.org/esaro/5482_HIV_AIDS.html) Accessed: May 20th, 2018.

World Health Organization (WHO): Global Health Observatory Data Repository. (http://apps.who.int/gho/data/node.main.620?lang=en) Accessed: May 20th, 2018.

Hung et al. (2008). Impact of long-term treatment with neurotoxic dideoxynucleoside antiretrovirals: implications for clinical care in resource-limited settings. HIV Med. 2008 Oct;9(9):731-7. doi: 10.1111/j.1468-1293.2008.00615.x.

Keswani et al. (2002). HIV-Associated Sensory Neuropathies. AIDS, 16(16):2105-2117

Maritz et al. (2010). HIV Neuropathy in South Africans: Frequency, Characteristics, and Risk Factors. Muscle Nerve. 2010 May;41(5):599-606. doi: 10.1002/mus.21535.