每年只需注射六次就可以預防愛滋病毒：這就是世界要負擔得起費用的藥物

勞拉·洛佩茲·岡薩雷斯 / 2022 年 8 月 2 日 / aidsmap / 財團法人台灣紅絲帶基金會編譯

  

南非治療行動運動主席 Sibongile Tshabalala 在 2022 年 AIDS 大會上領導抗議無法獲得可注射型的 PrEP。

照片©Jordi Ruiz Cirera/IAS

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每兩個月注射一次抗反轉錄病毒藥物cabotegravir，是世界上前所未有的預防愛滋病毒的最有效方法。使其負擔得起將部分取決於有多少仿製藥製造商將投資生產它——為此，世界必須展示市場的承諾：數百萬原本健康的人將在藥房或診所排隊快速每兩個月注射一次。

問題是：你如何為世界上大多數人還沒有見過的產品創造市場？

在男同性戀和雙性戀男性、跨性別女性和順性別女性中進行的兩項大規模臨床試驗發現，與每天服用 HIV 預防藥的人相比，接受抗反轉錄病毒藥物 cabotegravir 注射的人感染 HIV 的可能性降低了約 80%。世界衛生組織在關於注射劑使用的新指引中解釋說，這可能是因為它比日常用藥更容易使用。

根據本週在第 24 屆國際愛滋病大會上的演講中引用的未發表的數學模型的初步結果，在撒哈拉以南非洲迅速推出注射劑可能會導致該地區的新病例在未來大約 50 年內減少 27% （愛滋病 2022）。這項已提交給《剌胳針》的研究顯示，到 2070 年，廣泛使用長效愛滋病預防注射劑每年可以挽救約 75,000 人的生命。

儘管開發這種注射劑的 ViiV Healthcare 正在努力鼓勵仿製藥製造，但它很可能在未來三到五年內成為唯一的生產商。目前唯一獲准使用它的國家——美國——的官方價格標籤是每人每年 22,000 美元。儘管如此，如果其他抗反轉錄病毒藥物的定價趨勢有任何跡象，那麼即使在其他高收入國家，官方價格也會更低，許多付款人將協商大幅折扣。

ViiV 已經承諾向參與臨床試驗的 14 個國家註冊和供應注射用cabotegravir。其中近一半位於撒哈拉以南非洲。但為了向世界供應愛滋病預防注射劑，ViiV 將不得不提高產量。

「 ViiV 擁有非常強大的供應鏈，隨著時間的推移，我們將擴大我們的批量生產。我們願意與任何想要為 PrEP 採購長效 cabotegravir 的政府進行討論」， ViiV 發言人說。「然而，目前我們在供應方面面臨的一大挑戰是用於 PrEP 的長效 cabotegravir 的需求非常不確定」。

要讓 ViiV 在中短期內投資於昂貴的額外產能，它可能需要預先承諾從大型捐助者那裡購買，例如全球抗擊愛滋病、結核病和瘧疾基金以及美國總統的愛滋病緊急救援計劃 (PEPFAR) 。愛滋病預防組織 AVAC 的執行董事 Mitchell Warren 解釋說，他們可能會從 MedAccess 等社會投資基金獲得類似的承諾，就像他們為引入更好的抗瘧疾蚊帳所做的那樣。

最後，市場必須增長到足以容納至少三個額外的仿製藥供應商，這些供應商將準備在大約五年內分銷他們的產品。但在五年後，一種名為 lenacapavir 的實驗性、每年兩次的 HIV 預防注射劑也可能上市，可能會取代 cabotegravir 或減少其仿製藥的市場。

「如果你投資數千萬美元並開始看到這種低價的cabotegravir下線——突然間，lenacapavir顯示出安全性和有效性怎麼辦」？沃倫問道。

「這是一個風險」。

這也是為什麼他說尋求獲得愛滋病預防注射的機會不僅限於與cabotegravir有關。

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可以擴大新的自願許可

週四，ViiV Healthcare 宣布已與藥品專利池簽署了一項自願許可，允許 90 個中低收入和中低收入國家以及除利比亞以外的所有非洲國家獲得該藥物的仿製藥。藥品專利池是一個聯合國支持的公共衛生組織，旨在通過共享許可證來改善低收入和中等收入國家獲得負擔得起的、質量有保證的優先藥品版本。

然而，它不包括參加臨床試驗的巴西。擁有超過 100 萬愛滋病毒感染者的俄羅斯也被排除在外，阿爾巴尼亞、亞塞拜然和哈薩克斯坦等許多東歐國家也被排除在外。烏克蘭被包括在交易中，但這個飽受戰爭蹂躪的國家將成為向公共部門 HIV 項目支付 ViiV 特許權使用費總額的 5% 的國家之一。

相比之下，大約有 30 個國家的 ViiV 沒有為 HIV 預防注射劑申請專利，包括泰國、阿根廷、委內瑞拉和多明尼加共和國。理論上，注射 PrEP 的未來仿製藥生產商可以選擇向這些國家銷售。然而，這些國家大約一半是市場較小的小島國，在及時獲得藥物方面繼續面臨挑戰，部分係因這個原因。

作為許可的一部分，只有三個仿製藥生產商將能夠生產 ViiV 的注射劑。儘管這被批評為對該協議的限制，但藥品專利池政策負責人 Esteban Burrone 表示，該決定是謹慎平衡行為的一部分。

「我們需要申請並獲得許可的製造商在五年內投資結束時，在一個非常不確定的市場中進行重大投資」，Barrone 解釋說。

「一方面，我們正在努力平衡市場競爭的需求——因為這在將價格保持在可承受水平方面發揮著重要作用」，他繼續說道。「與此同時，我們希望防止出現將製造商擠出市場的情況」。

Burrone 補充說，藥品專利池和 ViiV 可以在需要時選擇將仿製藥生產商的池予以擴大。

仿製藥生產商也將考慮市場的潛在規模。雖然在過去十年中約有 280 萬人開始口服 PrEP，但製造商可能需要一個更大的市場才能使其值得一試。

「我們知道其中很多人只吃了一瓶藥就再也沒有回去過」，沃倫說。

「如果我們採用『最壞的情況』，並在口服 PrEP 的基礎上模擬對可注射 cabotegravir 的需求，你就不會支持任何生產」。

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費用：每位患者每年 60 美元是一個神奇的數字嗎？

在仿製藥製造商準備好之前，ViiV 將是唯一的製造商。該公司已宣布，它將向藥品專利池許可所涵蓋的 90 個國家提供尚未披露的注射劑降價。 ViiV 表示他們不會從這些銷售中獲利。

幾位消息人士告訴aidsmap，ViiV Healthcare 已經討論過在這些國家/地區可能會降低每人每年 240 美元的價格——幾乎是愛滋病預防藥仿製版本成本的五倍。

AVAC 是一個新的全球衛生合作夥伴聯盟的秘書處，該聯盟希望加快獲得長效愛滋病毒預防選擇——而不僅僅是cabotegravir。該聯盟包括藥品融資機制 Unitaid、世界衛生組織、全球基金以及最近的 PEPFAR。

Warren 說，即使對注射用 cabotegravir 的早期需求進行保守估計，有跡象表明 ViiV 可以以每人每年 120 美元左右的價格提供注射。

全球衛生組織克林頓健康獲取倡議 (CHAI) 估計，愛滋病預防注射劑的生產成本約為每人每年 16 美元——低於更常用的 PrEP 片劑的價格。但 ViiV 表示 CHAI 的預測大大低估了製造可注射 PrEP 的成本——這是一種製造更具挑戰性的產品。一位發言人說：「建議它可以以低於普通口服 PrEP 的價格製造是不現實的，後者是一種簡單的白色藥片」。

聯合國愛滋病規劃署和南非治療行動運動和健康 GAP 等許多倡導組織已公開要求 ViiV 將其折扣價降至每人每年 60 美元左右。據報導，PEPFAR 也一直在尋求類似的價格，但美國全球愛滋病協調員 John Nkengasong 在接受aidsmap 詢問時拒絕證實這一點。

南非治療行動運動主席 Sibongile Tshabalala 在國際愛滋病大會上領導抗議 ViiV 的愛滋病毒預防針價格過高。

「長效注射劑 PrEP 是一種改變遊戲規則的革命性愛滋病預防工具，但只要社區因為 ViiV 的貪婪而無法獲得該產品，世衛組織關於推出長效 cabotegravir 的指導方針就毫無意義」，Sibongile Tshabalala 說，南非的愛滋病毒倡導組織，治療行動運動。她是數十名抗議者中的一員，他們衝進會議，抗議無法獲得可注射的 PrEP。

國際愛滋病會議上提出的模型發現，南非還需要將注射 PrEP 定價在每人 60 美元左右，以使其對世界上最大的公共愛滋病毒項目具有成本效益。

對於未包括在 ViiV 與藥品專利池的交易中的國家，定價不太明確。 Mitchell Warren 認為，協議之外的國家可能會看到分層定價，這意味著各國將根據其感知的支付能力支付不同的價格。非洲以外的中上收入國家可能會被要求支付超過 240 美元的費用，但價格不太可能達到美國的官方價格標籤。

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ViiV 優先考慮試驗國家的監管批准

ViiV 已經在巴西、南非、波札那、辛巴威、馬拉威、肯亞和烏干達申請了愛滋病預防注射劑的監管批准。這些國家都參與了可注射cabotegravir的研究。

研究人員將在這些試驗的開放標籤階段追踪參與者長達兩年。在此之後，ViiV 將繼續為任何想要的試驗參與者提供注射劑，直到該藥物在該國註冊使用，公司發言人向aidsmap 證實。根據當地法律、基礎設施和供應鏈，公司如何做到這一點將因國家/地區而異。

沃倫解釋說，ViiV 還在澳大利亞註冊了注射劑的使用，並希望那裡的授權有助於促進使用澳大利亞批准的亞洲國家的准入，以加快當地批准。

Christine Malati 是美國開發署的高級藥劑師。 Malati 說，在 ViiV 尚未申請監管批准的國家，國家愛滋病委員會現在應該開始遊說藥物監管機構豁免，以確保及時獲得。

「我可以想像，在接下來的三年中，出於多種原因，我們將在低收入和中等收入國家看到更多的 cabotegravir PrEP 用戶」，沃倫說。「這就是顛覆了 COVID-19 [疫苗] 的經驗」。

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Cabotegravir 只是一個開始

世衛組織最近對約 900 家國際 PrEP 提供者進行的一項調查顯示，十分之七的人表示，如果他們能夠獲得 HIV 預防注射，他們將提供這種注射。

但只有大約一半的人知道它的存在。

爭取負擔得起的可注射 PrEP 的奮鬥是沃倫所說的「雞和蛋的情況」。在人們手中沒有產品的情況下，如何建立一個市場來吸引投資，在這種情況下，沒有簡單的答案，或者沒有背面。

「這是一個巨大的拼圖，我希望它只是一個適合三歲孩子的拼圖，它有四塊，其中一個是價格」，他說，「但它是一個 1000 塊的拼圖，而且就像是每一塊看起來都一樣」。

未來還會有其他謎題。四種新形式的長效可注射 PrEP 或植入型正在臨床試驗中，幾乎是實驗室測試的兩倍。

「這不僅適用於 cabotegravir」，Warren 解釋說。 「這是關於建立我認為的預防管道，我們可以透過它流動任何東西」。”

他繼續說：「我們可以想像，我們將為 cabotegravir 策略性地構建這些計畫，我們可以添加未來的注射選擇——我們可以走得更快」。

倡導者說，迫切需要獲得有效的預防工具。

「當我感染 HIV 時，我還是個小女孩，選擇有限」，Lillian Mworeko 在會議上對滿屋子的與會代表說。 Mworeko 是東非感染愛滋病毒的婦女國際社區的執行董事和創始成員。「那麼你們在這個房間裡的人和那些在董事會裡制定決策和政策的人，你們告訴了我們的事情，我們做到了」。

「你說，『不要懷孕』，我們沒有懷孕。然後你給我們買了預防母嬰傳播的服務，你說，『生孩子』」，她繼續說。 「我們生了孩子，我們盡一切努力讓他們保持 HIV 陰性」。

「今天，這些孩子正處於我們當中一些人被感染的年齡，我們卻沒有為他們準備預防的工具」，她說。「我們不能談論五年後的藥物取得」。

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Just six injections a year can prevent HIV: here’s what it will take for the world to afford them

Laura Lopez Gonzalez

2 August 2022

 

Sibongile Tshabalala, Chairperson of South Africa’s Treatment Action Campaign, leading the protest over lack of access to injectable PrEP at AIDS 2022. Photo©Jordi Ruiz Cirera/IAS

An injection every two months of the antiretroviral cabotegravir is the most effective way to prevent HIV that the world has ever seen. Making it affordable will depend, in part, on how many generic manufacturers will invest in producing it — and for that, the world must show the promise of markets: millions of otherwise healthy people who will line up at a pharmacy or clinic for a quick injection every two months.

The question is: how do you create a market for a product that most of the world has not yet seen?

Two large-scale clinical trials conducted among gay and bisexual men, transgender women and cisgender women found that those who received injections of the antiretroviral cabotegravir were about 80% less likely to contract HIV than those taking the daily HIV prevention pill. This is probably because it is easier to use than daily medication, the World Health Organization explains in new guidelines on the injection’s use.

Rapidly rolling out the injection in sub-Saharan Africa could lead to a 27% reduction in new cases in the region in the next roughly 50 years, according to the preliminary results of unpublished mathematical modelling quoted in presentations this week at the 24th International AIDS Conference (AIDS 2022). The study, which has been submitted to The Lancet, showed widespread access to long-acting HIV prevention injections could save about 75,000 lives annually by 2070.

Although ViiV Healthcare, which developed the injection, is working to encourage generic manufacturing, it is likely to be the sole producer for the next three to five years. The official price tag in the only country in which it is currently approved for use — the United States — is $22,000 per person annually. Still, if pricing trends around other antiretrovirals are any indication, official prices will be lower even in other high-income countries and many payers will negotiate substantial discounts.

ViiV has already committed to registering and supplying injectable cabotegravir to the 14 countries that were involved in clinical trials. Nearly half of these were in sub-Saharan Africa. But to supply the world with the HIV prevention injection, ViiV will have to ramp up production.

“ViiV has a very robust supply chain and we’ll be expanding our volume production over time. We’re open to discussing with any government that wants to procure long-acting cabotegravir for PrEP,” a ViiV spokesperson said. “However, one of the big challenges for us with supply at the moment is that demand for long-acting cabotegravir for PrEP is very uncertain.”

For ViiV to invest in expensive additional capacity in the short and medium term, it will probably need upfront commitments to purchase from large donors such as the Global Fund to Fight AIDS, TB and Malaria and the US President’s Emergency Plan for AIDS Relief (PEPFAR). They may get similar promises from social investment funds such as MedAccess, much like they did to introduce better malaria-busting bed nets, explains Mitchell Warren, executive director of the HIV prevention organisation AVAC.

Finally, the market will have to grow large enough to accommodate at least three additional generic suppliers that will be ready to distribute their products in around five years. But in five years’ time, an experimental, twice-a-year HIV prevention injectable called lenacapavir might also be coming to market, possibly unseating cabotegravir or reducing the market for generic versions of it.

“What if you invest tens of millions of dollars and begin to see this low-price cabotegravir coming off the line — and all of a sudden, lenacapavir shows safety and efficacy?” Warren asks.

“It’s a risk.”

It’s also why he says the quest for access to an HIV prevention injection can’t just be about cabotegravir.

New voluntary licence could be expanded

On Thursday, ViiV Healthcare announced that it had signed a voluntary licence with the Medicines Patent Pool to allow 90 low- and lower middle-income and all African countries except Libya to access generic versions of the drug. The Medicines Patent Pool is a UN-backed public health organisation to improve access to affordable, quality-assured versions of priority medicines in low- and middle-income countries through the sharing of licences.

It however excludes Brazil, for instance, which took part in clinical trials. Russia, home to more than one million people living with HIV, is also excluded as are many eastern European countries such as Albania, Azerbaijan, and Kazakhstan. Ukraine is included in the deal but the war-torn country will be among the ten countries that will pay ViiV royalties totalling 5% of net sales to public sector HIV programmes.

In contrast, there are about 30 countries in which ViiV has not patented the HIV prevention injection, including Thailand, Argentina, Venezuela and the Dominican Republic. In theory, future generic producers of injectable PrEP could choose to sell to these countries. However about half are small island nations with small markets that continue to face challenges in timely access to medicines partly for this reason.

As part of the licence, just three generic producers will be able to manufacture ViiV’s injection. Although this has been criticised as a limitation of the agreement, Medicines Patent Pool head of policy Esteban Burrone says the decision is part of a careful balancing act.

“We need the manufacturers who apply and get the licence to make significant investments with a very uncertain market at the end of that investment for five years,” Barrone explains.

“We’re trying to balance out the need, on the one hand, for competition in the market — because that plays a significant role in keeping prices to affordable levels,” he continued. “At the same time, we want to prevent a situation that will crowd out the manufacturers.”

Burrone adds that the Medicines Patent Pool and ViiV can choose to expand the pool of generic producers if needed. 

Generic producers will also be considering the potential size of the market. While about 2.8 million people have started oral PrEP in the last decade, manufacturers may need a much larger market to make it worth their while.

“We know a lot of those people had one bottle of pills and never went back again,” Warren says.

“If we took the ‘worst-case scenario’ and modelled demand for injectable cabotegravir on that for oral PrEP, you wouldn’t support any manufacturing.”

Cost: is $60 per patient per year the magic number?

Until generic manufacturers are ready, ViiV will be the sole manufacturer. The company has announced it will offer the 90 countries covered in the Medicines Patent Pool licence an as yet undisclosed reduced price on the injection. ViiV says they will not make a profit on these sales.

Several sources tell aidsmap that ViiV Healthcare has discussed a potentially reduced price in these countries of $240 per person annually — nearly five times the cost of generic versions of the HIV prevention pill. 

AVAC is the secretariat for a new coalition of global health partners hoping to speed up access to long-acting HIV prevention options — not just cabotegravir. The coalition includes medicine financing mechanism Unitaid, the World Health Organization, the Global Fund and, most recently, PEPFAR.

Warren says that even with conservative estimates of early demand for injectable cabotegravir, there are indications that ViiV could deliver the injection at about $120 per person per year.

Global health organisation the Clinton Health Access Initiative (CHAI) has estimated that the HIV prevention injection could be produced for about $16 per person per year – less than the price of more commonly used PrEP tablets. But ViiV says CHAI’s projections vastly underestimate the cost of making injectable PrEP – a much more challenging product to manufacture. “It’s not realistic to suggest it can be made for less than generic oral PrEP, which is a simple white tablet,” a spokesperson said.

UNAIDS and many advocacy organisations such as South Africa’s Treatment Action Campaign and Health GAP have publicly demanded ViiV drop its discounted price to about $60 per person annually. PEPFAR was also reported to have been seeking a similar price but US Global AIDS Coordinator John Nkengasong declined to confirm this when asked by aidsmap.

Chairperson of South Africa’s Treatment Action Campaign, Sibongile Tshabalala, leads a protest at the International AIDS Conference over ViiV’s high prices for its HIV prevention shot.

“Long-acting injectable PrEP is a game-changing revolutionary tool for HIV prevention but WHO guidelines for rolling out long-acting cabotegravir mean nothing as long as communities can’t get this product because of ViiV greed,” said Sibongile Tshabalala, chairperson of South Africa’s HIV advocacy group, Treatment Action Campaign. She was one of dozens of protestors who stormed a conference session to protest the lack of access to injectable PrEP.

Modelling presented at the International AIDS Conference found that South Africa would also need injectable PrEP to be priced at around US$60 per person to make it cost-effective for the world’s largest public HIV programme.

Pricing is less clear for countries not included in ViiV’s deal with the Medicines Patent Pool. Mitchell Warren believes countries outside the deal can expect to see tiered pricing, meaning countries would pay different prices depending on their perceived ability to pay. Upper middle-income countries outside of Africa would probably be asked to pay more than $240, but it is unlikely that prices would reach the official US price tag.

ViiV prioritises regulatory approval in trial countries

ViiV has already applied for regulatory approval for the HIV prevention injection in Brazil, South Africa, Botswana, Zimbabwe, Malawi, Kenya, and Uganda. These countries all took part in the studies for injectable cabotegravir.

Researchers will be following participants in the open-label phase of these trials for up to two years. After this, ViiV will continue to provide the injection for any trial participant who wants it until the drug is registered for use in the country, a company spokesperson confirmed to aidsmap. Just how the company does this will vary by country according to local laws, infrastructure and supply chains.

ViiV has also registered the injection for use in Australia and is hoping authorisation there will help facilitate access in Asian countries that use Australian approvals to fast-track local approval, Warren explains.

Christine Malati is a senior pharmacist for the United States Agency for Development. Malati says national AIDS councils in countries in which ViiV has not yet applied for regulatory approval should begin lobbying drug regulators now for waivers to ensure timely access.

“I can imagine that over the next three years, we will see more cabotegravir PrEP users in low- and middle-income countries than anywhere else for a number of reasons,” says Warren. “That’s the COVID-19 [vaccine] experience flipped.”

Cabotegravir is only the start

In a recent WHO survey of about 900 international PrEP providers, about seven out of ten said they would offer the HIV prevention injection if they had access to it.

But only about half knew that one existed.

The fight for affordable injectable PrEP is what Warren calls a “chicken and egg situation”. There’s no easy answer for how to build a market to entice investment without a product in people’s hands – or, in this case, backsides. 

“It’s a huge puzzle and I wish it were just one of those puzzles for a three-year-old, where it’s four pieces, and one of them was the price,” he says, “But it’s a 1000-piece puzzle and it’s like every piece looks the same.”

There will be other puzzles in the future. Four new forms of long-acting injectable PrEP or implants are in clinical trials and almost twice as many are in laboratory testing.

“This is not just for cabotegravir,” Warren explains. “It’s about building what I kind of think of as prevention pipes through which we can flow anything.”

He continues: “We could imagine that these programmes that we will have strategically built for cabotegravir, we could add future injectable options — and we could go even faster.”

Advocates say that there is an urgent need for access to effective prevention tools.

“When I got HIV, I was a young girl and there were limited options,” Lillian Mworeko told a room full of delegates at the conference. Mworeko is the executive director and founding member of the International Community of Women living with HIV in Eastern Africa. “Then you people here in this room and those who are in boardrooms making decisions and policies, you told us things and we did them.”

“You said, ‘Don’t get pregnant.’ We did not get pregnant. Then you bought us prevention of mother-to-child transmission services and you said, ‘get babies,’” she continued. “We got babies and we did everything to keep them HIV negative.”

“Today these children are at the age where some of us got infected and we don’t have tools for them,” she said. “We cannot talk about access in five years.”