Resisting stock-outs

Thandi Shabangu, a Treatment Action Campaign (TAC) member and community worker living in Gauteng, is one of the thousands of people living with HIV in South Africa who have been affected by recent stock-outsof antiretroviral (ARV) combination medicine lopinavir/ritonavir (LPV/r). Shabangu started taking ARVs in 2004. She switched to a second line regimen containing LPV/r, sold under the brand name Aluvia in 2006 after developing resistance to first-line ARVs following an interruption of her treatment during a period of hospitalisation for meningitis.

In 2015, Shabangu’s treatment was interrupted again – this time due to widespread stock-outs of LPV/r. Shabangu fears that the interruption could lead her to develop f urther resistance: ‘I’m no longer taking Aluvia because of the stockout. This problem is very big, because it’s a matter of life and death. If you don’t take your Aluvia, you are going to resist.’

Stock-outs of LPV/r have resulted in treatment interruptions for thousands of patients during 2015 who, like Shabangu, are receiving second-line ARV regimens through public sector health facilities. LPV/r is provided in standardised second-line regimens for children, adolescents and adults1 in South Africa, where approximately 200,000 of the 3 million people receiving ARVs require –second-line treatment.

During 2015, severe shortages of LPV/r (200/50mg and 100/25mg formulations) resulted in stock-outs of this medicine in facilities around the country. Between April and October 2015, stock-outs of LPV/r were reported by 57 facilities3 and four provincial depots to a civil society consortium monitoring medicine stock-outs in the country. The consortium was informed, in 65 percent of reports, that patients were being sent home from facilities with no supply of LPV/r and, in the other 35 percent of reports, that patients were being sent home from clinics with an inadequate supply.

Interruptions of ARV treatment due to stockouts are extremely problematic, both for patients receiving treatment and for the long-term sustainability of South Africa’s ARV programme.

Patients experiencing treatment interruption face increased risks of immunological failure, opportunistic infections, further resistance, and even death. In addition to severe health consequences, treatment interruptions can cause emotional and financial distress for people living with HIV and their families. Duringstock-outs, patients are often informed by healthcare workers that they should procure medications from private pharmacies during stock-outs, which is unaffordable for many. ‘When my Aluvia was finished I went to the clinic and they told me, “No, we don’t have Aluvia, so you’re supposed to go to the chemist to buy the Aluvia.” The challenge is, what if people don’t have money or parents or someone to help them get the medicine? For me I had that problem,’ Shabangu says.

Treatment interruptions also jeopardise the long term sustainability of the ARV programme in South Africa. Patients who experience treatment interruptions due to stock-outs may develop further resistance and require significantly more costly third-line regimens. Third-line ARV regimens procured for public sector use are currently 6.5 times more expensive than second-line regimens. Treatment interruptions may also cause patients’ previously suppressed viral loads to rebound – increasing their risks of onward transmission of HIV to their sexual partners when not utilising condoms consistently.

Clinicians and advocates further fear that stock-outs will impact negatively on patients’ long-term adherence. Lauren Jankelowitz, CEO of the HIV Clinicians Society of Southern Africa explains: ‘Part of the difficulty is that you’ve spent 10 years telling patients that you have to take every dose and you can’t miss and you can’t be late and it’s so important to adhere, and now we’re saying, “Oh, okay, well, if you miss a couple of doses it’s not the end of the world.” Psychologically it can be the end of the world for adherence.’

What caused the LPV/r stock-outs and what are potential solutions?

Stockouts of LPV/r have largely occurred as a result of AbbVie’s inability to provide adequate supply to meet need. AbbVie is currently the only supplier of LPV/r in South Africa, and holds multiple patent monopolies on formulations of this medicine, lasting until at least 2026. While AbbVie is the only supplier of LPV/r in South Africa, it is not the only supplier globally. Multiple generic suppliers of LPV/r products have been quality assured by the WHO, and some generic products have already been registered locally. Yet, to date, patent monopolies held by AbbVie in South Africa have blocked the use of registered generics to increase supply and curb stock-outs.

Given that AbbVie has been unable to ensure security of supply, mechanisms to facilitate use of generic LPV/r products in South Africa should be urgently pursued. Mechanisms to allow for use of generic products under patent protection include voluntary and compulsory licences. As their name suggests, ‘voluntary licences’ are licences that are granted voluntarily by the patent-holding companies to allow for production and use of generic products during periods of patent protection. Voluntary licences may be granted via agreements between patent holders and generic producing companies or via intermediary organisations, such as the Medicines Patent Pool (a UN backed, international voluntary licensing mechanism).

Via the Medicines Patent Pool (MPP), AbbVie has granted a voluntary licence for generic production and use of paediatric 40/10mg LPV/r tablets and suspension – formulations that are not produced or marketed by AbbVie. However, since the 2010 establishment of the MPP, AbbVie has refused to grant licences for generic production of 200/50mg and 100/25mg LPV/r formulations used in ARV regimens for older children, adolescents and adults.Given AbbVie’s refusal to voluntarily grant licences for generic production and use of 200/50mg and 100/25mg formulations, coupled with their inability to provide adequate supply, non-voluntary licences (known as compulsory licences) should be issued to allow for use of generic LPV/r products in South Africa.

On 26 October 2015, Médecins Sans Frontières (MSF) publicly called on the National Department of Health (NDOH) to issue a compulsory licence to allow for use generic LPV/r products in South Africa on the grounds that that public health demands are not being met to an adequate extent.

Compulsory licences (including public non-commercial or government use licences) are licences that allow for use generic versions of products during patent monopoly periods without the consent of the patent holder. These types of licences are allowed under international trade agreements (including WTO’s Agreement on Trade Related Aspects of Intellectual Property Rights [TRIPS]) and South Africa’s national laws to protect health. Compulsory licences can be issued to allow for generic manufacture of medicines for a range of reasons, including the inability of the patent holder to provide an adequate supply or market their products at reasonable and affordable prices. While South Africa has never granted a compulsory licence on a medicine, this safeguard has been used in many other parts of the world to improve medicine accessibility and affordability.

Following MSF’s call for compulsory licensing, the NDOH released a public statement re-iterating South Africa’s right to use safeguards in TRIPS to protect health, and noting it was considering voluntary licensing via the Medicines Patent Pool and/or the use of parallel importation to respond to stock-outs.

In a response to the NDOH statement, MSF emphasised its support of the NDOH’s willingness to explore TRIPS safeguards to increase LPV/r supply, but noted that AbbVie has repeatedly refused to grant adequate voluntary licences and therefore compulsory licensing by government is necessary to ensure supply. MSF further cautioned against the use of parallel importation to resolve South Africa’s current supply shortages of LPV/r, as parallel importation involves procuring the patent holder’s product (in this case AbbVie’s LPV/r) from other markets, which could lead to further shortages in other parts of the world and competition among countries for limited supply, given the fact that AbbVie’s failure to provide sufficient supply has also been reported in other countries such as Kenya, Tanzania, Uganda and Lesotho.

As ARV programmes in South Africa and other countries mature, demand for second and subsequent lines of ARV treatment will only increase, AbbVie’s failure to date to ensure adequate supply highlights the urgency of ensuring reliable and secure supply from more than one source for critical ARV medicines such as LPV/r.

How do the LPV/r stock-outs and MSF’s call for compulsory licensing relate to the Fix The Patent Laws campaign?

While South Africa’s current patent laws allow for compulsory licensing, the Fix The Patent Laws (FTPL) coalition has noted that legislative amendments should be adopted into South Africa’s national laws to allow for a simpler, more workable and expedited procedures for granting compulsory licences in the country. The FTPL coalition is a joint coalition of 18 patient groups working in the fields of cancer, mental health, diabetes, epilepsy, other non-communicable diseases, sexual and reproductive health, TB and HIV.11

In addition to simplifying procedures for granting compulsory licences, the coalition has recommended the full adoption into South Africa’s laws of safeguards to protect health allowed under the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS). In 2013, following advocacy of the FTPL coalition, the Department of Trade and Industry (DTI) released a draft National Policy on Intellectual Property committing to full adoption of TRIPS safeguards into South Africa’s national laws. Yet, two years after the release of the draft policy, the policy has not been finalised and bills to amend the Patents Act and related legislation to fully adopt TRIPS safeguards have not been brought before parliament. Further, since the 2013 release of the draft policy, the international pharmaceutical industry has lobbied against proposed reforms to protect health, and tried to undermine the FTPL coalition’s efforts through covert campaigns.

In October 2015, the FTPL coalition called upon the DTI for urgent action, and to end delays in patent law reform. A timeline of intellectual property reform was released by the coalition and, in response to the coalition’s letter to the DTI, the Minister of Trade and Industry wrote to the coalition, noting the final policy would be released in the first quarter of 2016. With high medicine prices creating hardship for people across the country, and in light of major supply shortages for critical life-saving drugs, the DTI must live up to this promise. The people of South Africa cannot afford to wait.

A summarised version of the detailed timeline of IP reform in SA is illustrated Below.

When will AbbVie’s patent monopoly on LPV/r actually expire?

For patient groups, departments of health and generic competitors alike, identifying when patent monopoly protection on medicines actually end is notoriously complex. In large part, this is due to the lack of transparency allowed by governments and international patent filling mechanisms (such as the Patent Cooperation Treaty) in patent applications.

Currently many patents are filed under obscure names with no mention of the medicine to which they are related and sometimes under no name, but rather the chemical structure of the compound to which the patent is related – known as Marakush claims.

To provide greater transparency on when monopoly periods expire on critical antiretroviral medicines, the MPP has created a global patent database which is available on their website.According to the database, in South Africa the initial compound patent on lopinavir will expire in 2017 and the initial compound patent on ritonavir was not granted. Yet additional secondary patents on heat stable and other formulations of ritonavir and LPV/r have been granted, lasting up until 2026.

In response to MSF’s call for compulsory licences on these products, AbbVie has publicly stated that its patent monopolies will expire in 2016.10 To ensure that confusing and non-transparent information about patents do not continue to block generic versions of these medicines – AbbVie should issue an official statement that its will not assert its patent monopolies on these products after 2016 and also sign a broad voluntary licence agreement with the Medicines Patent Pool to avoid unnecessary patent barriers and shortages in other relevant low- and middle-income countries.