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Pharmacovigilance and Post-Marketing Trials: Stavudine's Last Fight – Part II

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09:10, July 3 2018

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Guillaume Trusz, Antonia Wadley & Peter Kamerman continue their exploration into the recent post-marketing clinical trials for the HIV antiretroviral stavudine

In the previous article, we discussed the prominence of human immunodeficiency virus (HIV) infection in South Africa and some of the issues pertaining to the current treatment options. Throughout the last decade, HIV awareness and treatments have made great leaps forward, but unfortunately late presentation by infected individuals at clinics, and a lack of access to treatments have counterbalanced these advances.

In addition, for those who have managed to receive some form of treatment, a good number were faced with unfortunate adverse effects, such as toxic neuropathy. Furthermore, a significant percentage of people continue to experience the debilitating pain that frequently accompanies the neuropathy despite having changed treatment regimen.

HIV Remains Prevalent in Young Adults

One factor that makes HIV and HIV-neuropathy difficult to treat in sub-Saharan Africa is the lack of support for AIDS patients and the stigma that constantly surrounds them, especially in the most rural parts of the continent. In South Africa, HIV is most prevalent in young adults, particularly those who live in informal or township settings. People living with HIV/AIDS (PLWHA) often reveal that they are scared to disclose their HIV status to their family and friends out of fear of public humiliation and abandonment. Therefore, it is of no surprise that anxiety, depression, and fear are frequently comorbid with HIV.

Numerous individuals are unwilling to report their pain to their primary physician, one reason being that they associate pain with disease progression and they are not ready, neither physically nor psychologically, to deal with the greater repercussions that would entail. But if physicians are not notified of this pain felt by their patients, how can proper care be presented to them? This lack of reporting of pain may be exacerbated by the failure of overworked and under skilled (in terms of pain management knowledge) clinical staff to enquire about pain in their patients, and to assess and appropriately manage the pain if present.

There currently are no treatments or regenerative therapies for HIV distal sensory polyneuropathy or antiretroviral (ARV) toxic neuropathy. Also, the only symptom of the neuropathy that is amenable to treatment is pain, but most treatments that have been shown to be effective in other types of painful peripheral neuropathy (e.g. painful diabetic polyneuropathy, and post-herpetic neuralgia) have not been shown to perform better than placebos in patients with painful HIV neuropathy. Such ‘’failed” treatments include the widely available and cheap drug amitriptyline, and the much publicized neuropathic pain medication pregabalin. It is also worth noting that analgesics and anti-inflammatories that work for other types of pain, such as paracetamol (acetaminophen), and non-steroidal anti-inflammatory drugs (NSAIDS) have no proven efficacy for any type neuropathic pain.

The only treatment for painful HIV neuropathy that has shown any promise is the topical treatment, high-dose capsaicin patch. The capsaicin essentially denudes the upper layer of the skin and desensitizes cutaneous nociceptors (pain receptors), which helps relieve the pain sensation. Nevertheless, the results for this treatment have been inconsistent, and the drug is prohibitively expensive, and usually unavailable, in low- and middle-income countries.

Eliminate Stavudine Completely? Not So Fast

Now, despite all of this, the simplest option that comes to mind to limit the effects of stavudine is to fully eliminate its use in HIV treatments. Unfortunately, simply eliminating the use of the drug is not a straightforward task.

In 2002, Botswana became the first country in Africa to provide free universal access to HIV treatment. South Africa, along with a few other sub-Saharan countries, quickly followed. In 2003, the Operational Plan for Comprehensive HIV and AIDS Care, Management and Treatment for South Africa was proposed. The plan consisted in providing free ARV therapy to medically eligible patients at public health care facilities. The goal was to make HIV medication accessible to the majority of the population who could not afford private medical care. One of the key advantages of using stavudine as a frontline treatment is that its generic version is one of, if not the lowest costing HIV drug (much cheaper than generic versions of drugs used in place of stavudine, such as AZT and tenofovir).

In 2010, the World Health Organization (WHO) asked for low- and middle-income countries to phase out stavudine due to its long-term side effects. According to various government released HIV treatment guidelines, most sub-Saharan countries have done so. Botswana and Uganda have completely eliminated stavudine from their treatment plans. Other countries like Zambia and Malawi have limited the prescription of stavudine to very special circumstances. South Africa on the other hand, has had a much more difficult time phasing it out, the reason being cost containment.

Rise in Costs Hurting South Africa

Compared to Botswana, which has the largest gross domestic product (GDP) per capita of the African continent, and is dealing with a few hundred thousand individuals with HIV, South Africa is dealing with millions of patients, meaning a huge increase in cost and a drastic augmentation of the economic impact of this issue.

To make matters worse, a steady depreciation in the value of the South African Rand against the U.S. Dollar has not made matters easier. The resulting increase in costs of imported medical goods have made private health care even less affordable than it already was for most of the South African population, meaning there is even greater pressure on the public health system to meet the demands of HIV patients.

Beyond the high cost of medication, the non-drug costs, such as labor and in-patient care, also need to be accounted for. As for the HIV patients themselves, transport costs to and from the medical center, long waiting times, and lack of appropriate counseling hinder their access to treatment.

Now if treating the neuropathic pain and fully eliminating the drug are currently not strong possibilities, then where do we go from here?

 

Guillaume Trusz

Antonia Wadley

Peter Kamerman

 

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

 

*Click here to read the conclusion of this three-part exclusive.

 

PHOTO CREDIT: Nicholas Raymond

 

References

Central Intelligence Agency (CIA). The World Factbook: HIV/ AIDS – Adult Prevalence Rate. (https://www.cia.gov/library/publications/the-world-factbook/rankorder/2155rank.html)   Accessed: May 20th, 2018.

Jelsma et al. (2005).An investigation into the health-related quality of life of individuals living with HIV who are receiving HAART.AIDS Care, 17(5): 579-588

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

Makoae et al. (2005). The Symptom Experience of People Living With HIV/AIDS in Southern Africa. JANAC Vol. 16, No. 3, doi: 10.1016/j.jana.2005.03.005

Simpson et al. (2008).Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy.Neurology, 70: 2305-2313, doi: 10.1212/01.wnl.0000314647.35825.9c

Simpson et al. (2010).Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial. Neurology, 74(5):413-420, doi: 10.1212/WNL.0b013e3181ccc6ef

Wadley et al. (2016). Resilience does not explain the dissociation between chronic pain and physical activity in South Africans living with HIV. PeerJ. 4:e2464; doi: 10.7717/peerj.2464

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