Several African countries have found success in eliminating stavudine treatments. South Africa, on the other hand, has struggled to overcome stavudine, and several scientists and researchers have taken on the problem head-on via dose optimization.

When it comes to treatment optimization, factors such as dose reduction, reformulation and process chemistry can be considered. Over the years, a few academic researchers have conducted new trials to determine whether a reduction in the dose of stavudine prescribed would still provide the needed HIV treatment all the while limiting the effects of the toxic neuropathy. Most studies have demonstrated that lowering the dose actually provided equal efficacy and improved safety, including lower rates of neuropathy.

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As opposed to clinical trials performed for novel drug products, conducting post-marketing trials (or phase IV clinical trials) is much more straightforward. Years of post-marketing surveillance have helped us hone in and focus on specific ARV symptoms. Instead of actively searching for any possible signs of drug adverse effects, we know exactly what symptoms to look for.

Dose Reduction in Stavudine Could be the Answer

Post-marketing surveillance has also allowed us to study the effects of the drug in the general population (such as children and pregnant women, which are often excluded during the original trials) and in a non-controlled, real-life environment. Doing so has granted us a better understanding of certain contraindications and how other prescription drugs can be antagonistic. Long-term surveillance often leads to the detection of novel adverse effects that were not detectable in the original clinical trials due to inadequate sample sizes and limited timelines.

In such trials – academic and post-marketing – there are no major monetary incentive to be gained by a big pharmaceutical company or a rush to get the product out to market as fast as possible. Moreover, post-marketing trials are much simpler as we know the drug works and there are no pre-clinical animal studies required or need for proof of concept. The majority of the time, post-marketing surveillance is important in the first couple of years following the original marketing date. In this case, monitoring HIV-neuropathy is quite vital as its effects continue to have a strong impact on the HIV population.

One trial that has been particularly intriguing was a comparison of dose reduction in stavudine (a halving of the dose to 20 mg bid) compared to the effects of tenofovir (both in combination with lamivudine and efavirenz as HAART treatments). This multi-site, international trial hopes to show that low doses of stavudine will provide patients with the needed HIV defense all the while limiting adverse effects.

Reducing the Cost of Drugs

Trials such as this one have met heavy criticism from several health organizations. Their key argument is the fact that no reduction in price will ever compensate for the drug’s toxicity. This of course opens up the debate of only treating a portion of the HIV population with non-toxic medication, or treating most of the population with a toxic medication, but having to face the repercussions that follow. Nevertheless, when cost is a major variable everything is up for grabs.

Since the inception of this trial, numerous changes have taken place on the ARV front. Price decreases in AZT and tenofovir have dramatically reduced the financial barriers to their routine use and therefore for the need for stavudine. In addition, various independent third parties and organizations have contributed to the HIV fight, reducing the financial burden on governments to provide these other treatments. Thanks to these initiatives, as well as improved manufacturing practices, stavudine has seen its number of prescriptions significantly decreased.

Limiting the cost of the drugs used in HIV treatment, would allow South Africa to allocate more resources towards the prevention of further cases of HIV. Expanding access to pre-exposure prophylaxis (PrEP) and birth control, as well as increasing rates of male circumcision have had somewhat positive effects. Ongoing research has led physicians and scientists to begin finding ways of curbing vertical disease transmission (mother to child), hopefully dramatically reducing the rates of pediatric AIDS in the near future. In addition, a massive clinical trial consisting of several thousands of participants is currently underway in South Africa, potentially holding the key to the future HIV vaccine.

What Future for Stavudine?

Regardless of the outcome of the optimization trial, stavudine will still play a role in HIV treatment, even if minor. Other medications are not without their own adverse effects, and thus stavudine can be used as a short-term replacement in patients with contraindications to other medications.

AZT has been shown to cause myelosupression (which could cause anemia, leucopenia, or many other medical conditions), and findings have revealed tenofovir to be nephrotoxic in certain individuals. Short term, low dose stavudine treatments could offer the patients treatment all the while limiting the possible adverse effects.

Despite its diminishing role, stavudine has had a huge impact on the global HIV population and without it, the goal of ending the AIDS epidemic by 2030 would never have been a possibility.

 

Guillaume Trusz

Antonia Wadley

Peter Kamerman

 

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

 

References

1) Andrieux-Meyer et al. (2012). Why it’s time to say goodbye to stavudine … everywhere. South Afr J HIV Med. 2012 Mar 13;13(1):776. doi: 10.4102/sajhivmed.v13i1.155.

2) Clayden, P. (2016). Fit For Purpose: Antiretroviral Treatment Optimization. Treatment Action Group (TAG) Pipeline Report 2017.

3) ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02670772). Accessed: May 20th, 2018.

4) Hill, A. (2013). Optimizing HIV Treatment. CurrOpin HIV AIDS. 2013 Jan;8(1):34-40. doi: 10.1097/COH.0b013e32835b7f28.

5) Magula N., & Dedicoat M. (2015). Low dose versus high dose stavudine for treating people with HIV infection. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD007497. doi: 10.1002/14651858.CD007497.pub.2.

6) Meintjes et al. (2017). Adult Antiretroviral Treatment Guidelines 2017.South Afr J HIV Med. 2017 Jul 15;18(1):776. doi: 10.4102/sajhivmed.v18i1.776.