喬治貝洛 (George Bello) 博士在 CROI 2024。攝影：Roger Pebody。
上週的反轉錄病毒和伺機性感染會議(CROI 2024) 上的許多演講探討了愛滋病毒是否開始對多替拉韋(dolutegravir) 產生抗藥性，多替拉韋是世界上使用最廣泛的抗反轉錄病毒藥物之一。
世界大部分地區的指引建議將多替拉韋（或其近親比克替拉韋bictegravir）作為大多數人首次愛滋病毒治療方案的組成部分。 世界衛生組織建議所有人群使用它，如果它不是個人一線愛滋病治療的一部分，它通常會成為其二線治療方案的一部分。 大多數低收入和中等收入國家現已改用替諾福韋、拉米夫定和多替拉韋 (tenofovir, lamivudine and dolutegravir, TLD) 的複方藥物，其中包括世界上最大的抗反轉錄病毒治療 (ART) 計畫所在地南非。
這是可能的，因為dolutearavir的製造商ViiV 允許仿製藥製造商生產它，但首先選擇多替拉韋是因為研究顯示它幾乎沒有副作用——在早期對出生缺陷的恐慌被證明是錯誤的之後——而且因為多替拉韋呈現對愛滋病毒抗藥性的發展構成非常高的障礙。
然而，多替拉韋現在已成為全球抗反轉錄病毒治療的基石，因此計畫需要密切關注愛滋病毒增加對多替拉韋抗藥性的任何跡象。 上週，世界衛生組織發布了一份報告，引發人們對最近觀察性調查發現「愛滋病毒對多替拉韋抗藥性水平超過臨床試驗中觀察到的水平」的擔憂。 第二天，CROI 2024 上的整個海報討論會特別討論了這個問題。
引言
南非斯泰倫博斯大學的 Gert van Zyl 博士介紹了本次會議，他評論了多替拉韋如何成為「統治一切的單一藥物」。 他說，這次會議是由研究中的多替拉韋抗藥性報告引起的，例如這項研究，主要來自高收入國家和B 病毒分支，其中14% 的ART 失敗患者存在整合酶鏈轉移抑制劑(INSTI) 抗藥性突變，儘管只有 1% 對多替拉韋具有高度抗藥性。
他說，理論上，在低收入環境中，這個問題可能會更嚴重，因為那裡有更多的人改用多替拉韋。 有些早在六年前就被轉換了，通常不管它們在轉換時是否受到病毒抑制，並且缺乏持續的病毒量監測。 此外，HIV 的非 B 演化支可能具有不同的整合酶抗性模式。
他補充說，要判斷抗藥性問題的嚴重程度並不容易。 在報告多替拉韋抗藥性時，存在一個問題，即使用哪個分母——是每個人都在服用該藥物，只有病毒學失敗的人，還是只有懷疑有抗藥性的人？ 然後還有一個使用什麼分子的問題——是否計算任何多替拉韋突變（即使沒有失去敏感性），只計算高水平的突變，還是只計算明顯失去敏感性的情況？
Van Zyl 列出了史丹佛大學抗藥性資料庫收集的迄今為止最常見的抗藥性突變。 在八個被認為是「主要」的突變中，本次會議中介紹的研究中最常見的是HIV 整合酶中第66、118、138、148 和263 位元氨基酸的變化。一些研究也發現了第66、118、138、148 和263 位元氨基酸的突變。147，不在史丹佛大學的名單中。
這些突變的「電話號碼」值得記住，與其說它們本身，不如說是因為它們在不同的研究中似乎以非常不同的模式發生，並且似乎受到人們是否第一次服用嵌合酶鏈轉移抑制劑 (INSTI) ，以及是否有其他突變，甚至是對其他藥物類別。
一般來說，顯著的多替拉韋抗藥性似乎仍然不常見，甚至可以透過改善依從性來逆轉。 但在過去兩年裡，這種情況變得越來越普遍，而且包括兒童在內的某些群體似乎更容易出現這種情況。
兒童多替拉韋抗藥性
一項研究專門針對馬拉威的兒童。 馬拉維國際健康培訓和教育中心的 George Bello 博士在會議上表示，要納入這項研究，兒童必須年齡在 2-14 歲，服用多替拉韋超過 9 個月，並且最近一次接受過治療。病毒量超過1000，在為孩子和家長提供依從支持後再次測試時，病毒量仍超過1000。
在 CROI 2024 上，喬治‧貝洛 (George Bello) 博士與aidsmap的羅傑‧佩博迪 (Roger Pebody) 談論了馬拉威的多替拉韋抗藥性。
此樣本僅代表馬拉威感染愛滋病毒的兒童的一小部分。 最新統計有 53,843 個感染愛滋病毒的兒童，其中三分之二 (35,352) 正在接受抗病毒治療，99% 正在接受多替拉韋治療。 這項研究招募了 302 名兒童，他們在馬拉威 25 個最大的愛滋病毒診所中的 19 個診所就診。 經過依從性諮詢後，169 人（56%）再次實現了病毒抑制。
其餘 133 名兒童則接受了每種抗反轉錄病毒 (ARV) 藥物類別的抗藥性測試。 四分之三的人被發現至少有一種抗藥性突變，但對兩類反轉錄酶抑制劑的抗藥性更為常見，其中65.5% 對非核苷反轉錄酶抑制劑(NNRTI) 具有抗藥性，42% 對核苷反轉錄酶抑制劑（NRTI）具有抗藥性。 相較之下，只有 16% 的人有顯著的 INSTI 突變。 蛋白酶抑制劑 (PI) 突變更為罕見，為 5%。
在 18 名成功定序 INSTI 抗藥性突變的兒童中，出現了兩種截然不同的模式。 11 名兒童在 263 位點出現抗藥性突變，5 名兒童在 138 位點出現抗藥性突變。只有 1 名兒童沒有出現這兩種突變，而在 9 例病例中，263 位點突變是唯一的突變。 我們將再次遇到這些突變。
從服用多替拉韋的 35,300 多名兒童中，這 18 名兒童並無法代表高程度抗藥性的總和； 但它確實顯示，雖然多替拉韋抗藥性仍然不常見，特別是與多年來以 NNRTI 為基礎的治療方案相比，但它並非是微不足道的。
來自賴索託的第二項研究暗示兒童可能比成人面臨更大的風險。 瑞士巴塞爾大學的 Niklaus Labhardt 教授進行的這項研究是在該國最東部的兩個省份進行的。 該群體包括 17,724 名成員，但其中不到 3% 是兒童。
為了進行抗藥性測試，世代成員必須從基於 NNRTI 的治療方案改為 TLD，並且連續兩次病毒量低於 50 或一次超過 500，最後一次病毒量在轉換後超過 16 個月進行。在 15,299 名轉換者中，151 人符合資格，78 人進行了抗藥性測試。 其中，只有8 名(10%) 具有多替拉韋抗藥性，但其中兩名是9 歲和7 歲的男孩- 25% 的人具有多替拉韋抗藥性，而其中不到3%是兒童。 在多變量分析中，與年齡的相關性並沒有保持統計顯著性，因為兒童太少，唯一仍然顯著的其他特徵是在由護士領導的當地中心而不是在三個地區醫院之一接受治療。
另外兩項非洲研究
另外兩項研究來自非洲成年人。 肯亞是最早於2017 年推出TLD 的國家之一。肯亞衛生部的Leonard Kingwara 博士對55 名使用TLD 且病毒載量超過200 的人的樣本進行了檢測。55 個樣本中的44 個樣本回傳了有效抗藥性結果（低病毒量的樣本通常很難測試）。 在 44 例患者中，有 8 例 (14.5%) 存在多替拉韋抗藥性突變。 在開始TLD 時剛開始接受ART 的12 名患者中，只有1 名出現了抗藥性，但在先前接受過NNRTI 治療方案的31 名患者中，有7 名（近四分之一）出現了耐藥性。
與馬拉威的研究一樣，這裡看到了兩種不同抗性突變模式的相同模式。 所有 7 名有 NNRTI 經驗的人都有一些突變，其中包括第 138 位的突變（通常至少還有一個其他突變）。 相較之下，先前未接受過 ART 治療且對多替拉韋有抗藥性的患者是唯一在 263 位發生突變的患者，且僅在該位置發生突變。
相較之下，尚比亞和馬拉威的一項研究發現，在 2,833 名從 TLD 轉向的人中，只有兩人對多替拉韋具有顯著抗藥性。
誇祖魯納塔爾大學的理查德·萊塞爾斯博士表示，在這種轉變兩年後，他們只發現了92 人的病毒載量超過400，分別佔馬拉維和尚比亞人口的4.7% 和1.8%。 差異是由於贊比亞的病毒量可檢測到的人沒有資格進行轉換，這與馬拉威不同，這是病毒學失敗的一個明顯風險因素，使失敗的幾率增加了七倍。
62 人的病毒量超過 1000，45 個樣本已成功定序。 其中，只有兩人具有高程度的多替拉韋抗藥性。 在這兩種情況下，抗性突變都位於 138 位，同時至少還有一個其他主要突變，但不是 263 位突變。
墨西哥出現多替拉韋(dolutegravir)和比克替拉韋(bictegravir)抗藥性
在大西洋彼岸，一項整合酶抑制劑抗藥性研究包括兩種二線 INSTI：多替拉韋和比克替拉韋。 墨西哥城薩爾瓦多祖比蘭國家醫學和營養科學研究所的Luis Soto-Ramirez 博士在會議上表示，墨西哥34 萬名愛滋病毒感染者中約有87,000 人正在服用基於多替拉韋或比克替拉韋的治療方案。 許多人不是從 NNRTI 或 PI 轉向，而是從基於兩種早期 INSTI（拉替拉韋raltegravir和艾維拉韋elvitegravir）的治療方案轉向。
該研究所能夠聚集 100對比克替拉韋或多替拉韋經歷過病毒學失敗的人進行的抗藥性測試。 其中，75 人之前也曾接受一線 INSTI 治療失敗。 研究小組成功對 100 個樣本中的 79 個樣本進行了抗藥性突變定序，並發現了 20 個樣本存在原發突變。
與其他研究一樣，INSTI 抗藥性分為兩種模式： 263位突變的抗藥性和無突變的抗藥性。 在 7 個帶有 263 突變的樣本中，有 4 個來自服用比克替拉韋的人。 其中，所有這些都在第 50 位點有一個額外的突變，該突變不被算作抗性突變，而是以病毒量的減少來取代。 具有這種「M50I」突變的人的平均病毒量為 2250。除了一名服用 bictegravir 的人外，所有其他人都只有這兩種突變。
相較之下，服用多替拉韋的三人分別有五種、六種和九種突變。 具有 9 個突變的人也有 M50I，導致病毒量較低，但具有 6 個和 5 個突變的人的病毒量分別為 35,000 和 300,000。 攜帶 263 突變的人中沒有人再服用過 INSTI。
另一種模式是由 7 個人組成的一組，他們都在 140 和 148 位元發生突變，還有 4 個人在 138 位元發生突變。 這些突變被認為賦予了對多替拉韋最高程度的抗藥性。 七人中的四人還服用了第一代 INSTI 拉替拉韋。
雖然這種模式的頻率似乎沒有增加，但 263 突變卻變得更加頻繁。 在2019-2021 年之前的研究中，只有0.3% 的抗藥性測試出現了這種模式，在2021-22 年收集的樣本中，這一比例為5%，在2023 年收集的樣本中，這一比例為10%。因此，這種突變似乎是第一次對多替拉韋或比克替拉韋 (dolutegravir or bictegravir) 產生INSTI抗藥性的特定訊號：，並且對後者的損害可能較小。
另一個有趣的事實是，對11 名INSTI 抗藥性患者的NRTI 突變也進行了定序，結果沒有一人對拉米夫定/恩曲他濱 ( lamivudine / emtricitabine) 產生M184V/I 抗藥性突變，儘管這是最常見的NRTI突變，並且儘管11 人中大多數人有其他突變。 到目前為止，對此還沒有任何解釋，儘管已知 M184V 可以降低病毒量，因此可能使 HIV 更難跨越對 INSTI抗藥性上極高的屏障。
多替拉韋之後會發生什麼事？
最後，如果人們確實經歷了二線 INSTI 治療失敗，他們有哪些治療選擇？ 開普敦大學的趙英博士進行了一項研究，觀察了二線蛋白酶抑制劑療法失敗的患者——通常是加強洛匹那韋 (lopinavir) 治療。 在 355 人中，234 人對蛋白酶抑制劑有抗藥性突變。 其中，133 人改用多替拉韋，而 101 人改用被視為三線 PI 的強化達蘆那韋 (boosted darunavir)。 轉用 TLD 的人也與另外 121 名二線 PI 治療失敗但沒有 PI 抗藥性突變的人進行了比較。
繼續使用舊的 PI 效果並不好； 12 個月後，儘管在基準線時沒有抗藥性，但只有 35% 的人抑制了病毒，而轉向 TLD 的人有 77%。
然而，改用加強版達蘆那韋與改用多替拉韋一樣有效。 儘管有 PI 抗藥性突變，但服用多替拉韋和達蘆那韋的患者在 12 個月時仍保持病毒檢測不到狀態，分別為 89% 和 92%。 這似乎顯示，對於少數二線 INSTI 治療方案停止起作用的人來說，加強版達蘆那韋有可能成為一種挽救療法，
參考文獻：
Van Zyl F 會議概述 – 資源有限環境中的多替拉韋抗藥性。 逆轉錄病毒和機會性感染會議，丹佛，主題討論，2024 年 11 日。
Bello G et al. 馬拉威因治療失敗而接受調查的兒童中出現了新出現的多替拉韋抗藥性。 反轉錄病毒和伺機性感染會議，丹佛，摘要 187，2024 年。
Labhardt ND et al. 賴索托新出現的多替拉韋抗藥性。 反轉錄病毒和伺機性感染會議，丹佛，摘要 678，2024 年。
Kingwara L et al. 在肯亞接受基於 DTG 的 ART 時，先前有抗病毒治療經歷且病毒血症的患者出現 DTG 抗藥性。 反轉錄病毒和伺機性感染會議，丹佛，摘要 677，2024 年。
Lessells RJ et al. 常規改用基於多替拉韋的一線 ART 兩年後，病毒血症和抗藥性。 反轉錄病毒和伺機性感染會議，丹佛，摘要 676，2024 年。
Soto-Ramirez LE et al. 墨西哥 PLWH 對第二代 INSTI 的抗藥性：R263K 突變體的出現。 反轉錄病毒和伺機性感染會議，丹佛，摘要 679，2024 年。Zhao Y et al. 替諾福韋-拉米夫定-多替拉韋治療基於 PI 的二線 ART 失敗的病毒學結果。 反轉錄病毒和伺機性感染會議，丹佛，摘要 680，2024 年。
The cornerstone of HIV treatment may be losing some of its power: will dolutegravir resistance become a problem?
Dr George Bello at CROI 2024. Photo by Roger Pebody.
A number of presentations at last week’s Conference on Retroviruses and Opportunistic Infections (CROI 2024) looked at whether HIV is starting to develop resistance to dolutegravir, one of the most widely used antiretrovirals in the world.
Guidelines in most parts of the world recommend dolutegravir (or its close cousin, bictegravir) as a component of most people’s first HIV treatment regimen. The World Health Organization recommends it for all populations, and if it wasn’t part of a person’s first-line HIV treatment, it will usually be part of their second-line regimen. The majority of low- and middle-income countries have now switched to a combination pill of tenofovir, lamivudine and dolutegravir (TLD), including South Africa, home of the world’s largest antiretroviral therapy (ART) programme.
This was possible due to dolutearavir manufacturers ViiV allowing generic manufacturers to make it, but dolutegravir was chosen in the first place because studies showed that it was both pretty free of side effects – after an early scare about birth defects was disproved – and because dolutegravir appears to pose a very high barrier to the development of HIV drug resistance.
However, dolutegravir is now such a keystone of ART worldwide that programmes need to keep a careful watch for any sign of an increase in dolutegravir-resistant HIV. Last week, the World Health Organization issued a report raising concerns that recent observational surveys have found that “levels of HIV dolutegravir resistance are exceeding levels observed in clinical trials”. The next day, an entire poster discussion session was devoted to the issue at CROI 2024.
Introduction
Dr Gert van Zyl of Stellenbosch University in South Africa introduced the session by commenting how dolutegravir had become the “one drug to rule them all”. He said the session had been prompted by reports of dolutegravir resistance in studies such as this one, mainly from high-income countries and with clade B virus, where 14% of people with ART failure had integrase strand transfer inhibitor (INSTI) resistance mutations, though only 1% had high-level resistance to dolutegravir.
He said that the problem could in theory be worse in lower-income settings where far more people have been switched to dolutegravir. Some were switched as long as six years ago, often regardless of whether they were virally suppressed at the time they switched, and in the absence of ongoing viral load monitoring. In addition, non-B clades of HIV might have different integrase resistance patterns.
It was not easy, he added, to judge the degree to which resistance was a problem. There is a problem of which denominator was used when reporting the prevalence of dolutegravir resistance – was it everyone on the drug, only people with virological failure, or only ones suspected of having resistance? Then there was also a problem of what numerator was used – was any dolutegravir mutation counted (even with no loss of susceptibility), only mutations classed as high level, or only cases where there was clear loss of susceptibility?
Van Zyl listed the resistance mutations most commonly seen so far, as collected by the Stanford University Resistance Database. Among eight regarded as ‘major’, the ones seen most often in the studies presented in this session were changes to the amino acids in HIV’s integrase enzyme at positions 66, 118, 138, 148 and 263. Several studies also saw a mutation at position 147, not in Stanford’s list.
These ‘phone numbers’ of mutations are worth remembering not so much in themselves as because they seem to occur in very different patterns in different studies, and seem to be influenced by whether people are taking INSTIs for the first time or not, and whether they have other mutations, even to other drug classes.
In general, significant dolutegravir resistance still seems to be uncommon, and can even be reversed with improved adherence. But it has got more common in the last two years, and certain groups, including children, seem more prone to it.
Dolutegravir resistance in children
One study exclusively concerned children in Malawi. Dr George Bello of the Malawian International Training and Education Center for Health told the conference that to be included in the study, children had to be aged 2-14, to have been on dolutegravir for more than nine months, and to have had a latest viral load of over 1000, which was still over 1000 when tested again after adherence support for child and parent.
At CROI 2024, Dr George Bello spoke to aidsmap’s Roger Pebody about dolutegravir resistance in Malawi.
The sample represents a very small proportion of children with HIV in Malawi. At the latest count there are 53,843 children with HIV, of whom two-thirds (35,352) are on ART, 99% on dolutegravir. This study enrolled 302 children attending 19 of the 25 largest HIV clinics in Malawi. After adherence counselling, 169 (56%) achieved viral suppression again.
The remaining 133 children had tests for drug resistance to every antiretroviral (ARV) drug class. Three-quarters were found to have at least one resistance mutation, but resistance to both classes of reverse transcriptase inhibitors was far more common, with 65.5% having resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 42% to nucleoside reverse transcriptase inhibitors (NRTIs). In contrast, only 16% had significant INSTI mutations. Protease inhibitor (PI) mutations were even rarer at 5%.
Of 18 children with successfully sequenced INSTI resistance mutations, two quite separate patterns emerged. Eleven children had the resistance mutation at position 263 and five had one at position 138. Only one child had neither of these mutations and in nine cases the 263 mutation was the only one. We’ll encounter these mutations again.
Eighteen children out of more than 35,300 on dolutegravir cannot be the sum total with high-level resistance; but it does indicate that, while dolutegravir resistance is still uncommon, compared especially with the legacy of years of NNRTI-based regimens, it is not insignificant.
A second study hinting that children might be more at risk than adults came from Lesotho. This study by Professor Niklaus Labhardt of the University of Basel in Switzerland was of a cohort in the two easternmost provinces of the country. This cohort includes 17,724 members but under 3% of them are children.
To be tested for resistance, cohort members had to have changed from NNRTI-based regimens to TLD, and to have had two successive viral loads below 50 or one over 500, with the last taken more than 16 months after switching.
Of 15,299 who switched, 151 were eligible and 78 had a resistance test. Of these, only eight (10%) had dolutegravir resistance, but two of these were boys aged nine and seven – 25% of those with dolutegravir resistance in a cohort of whom less than 3% are children. The association with age did not stay statistically significant in multivariate analysis because there were so few children, and the only other characteristic, which remained significant, was to have been treated in a nurse-led local centre rather than one of the three regional hospitals.
Two more African studies
Two more studies came from adults in Africa. Kenya was one of the first countries to roll out TLD, in 2017. Dr Leonard Kingwara of the Kenyan Health Ministry tested samples from 55 people who were on TLD and had viral loads over 200. Forty-four of the 55 samples returned a valid resistance result (it is often difficult to test samples with low viral loads). Of the 44, eight (14.5%) had dolutegravir resistance mutations. Only one of the 12 who were new to ART when they started TLD had resistance, but, seven of the 31 (nearly a quarter) who had been on previous NNRTI-based regimens had resistance.
The same pattern of two different resistance mutation patterns was seen here as in the Malawi study. All seven of the people with prior NNRTI experience had a handful of mutations that included the one at position 138 (and usually at least one other). In contrast the one previously ART-naïve person with dolutegravir resistance was the only one with a mutation at position 263, and only at that position.
In contrast, a study from Zambia and Malawi found only two people with significant dolutegravir resistance among 2833 people who had switched from TLD.
Dr Richard Lessells of the KwaZulu Natal University said that two years after the switch they only found 92 people with viral loads over 400, representing 4.7% of the people in Malawi and 1.8% in Zambia. The difference was due to people with detectable viral loads in Zambia not being eligible for switching, unlike in Malawi, and this was the one clear risk factor for virological failure, increasing the odds of failure sevenfold.
Sixty-two people had a viral load over 1000 and 45 samples were successfully sequenced. Of these, only two had high-level dolutegravir resistance. In both cases the resistance mutation was at position 138 along with at least one other major mutation, but not the 263 mutation.
Emergent dolutegravir and bictegravir resistance in Mexico
Across the Atlantic, a study of integrase inhibitor resistance included both of the second-line INSTIs, dolutegravir and bictegravir. Dr Luis Soto-Ramirez of the Salvador Zubiran National Medical and Nutrition Science Institute in Mexico City told the conference that about 87,000 of the 340,000 people living with HIV in Mexico are now taking regimens based on dolutegravir or bictegravir. Many have switched, not from NNRTIs or PIs, but from regimens based on the two earlier INSTIs, raltegravir and elvitegravir.
The institute was able to gather 100 resistance tests from people who had experienced virological failure on bictegravir or dolutegravir. Of these, 75 had previously also had treatment failure on the first-line INSTIs. The team managed to successfully sequence 79 of the 100 samples for resistance mutations and found 20 with primary mutations.
As in other studies, INSTI resistance fell into two patterns; resistance with the mutation at position 263 and resistance without it. In the seven samples with the 263 mutation, four were from people on bictegravir. Of these, all had an additional mutation at position 50 which is not counted as a resistance mutation but instead reduces the viral load. The average viral load in the people with this ‘M50I’ mutation was 2250. All but one of the people on bictegravir had only these two mutations.
In contrast the three people on dolutegravir had five, six and nine mutations respectively. The person with nine mutations also had M50I, resulting in a low viral load, but the people with six and five mutations had viral loads of 35,000 and 300,000 respectively. None of the people with the 263 mutation had taken another INSTI.
The other pattern was a group of seven people who all had mutations at positions 140 and 148 and four at position 138 too. These mutations are the ones seen as conferring the highest-level resistance to dolutegravir. Four of the seven had also taken the first-generation INSTI raltegravir.
While the frequency of this pattern did not appear to be on the increase, the 263 mutation has become more frequent. This pattern was seen in just 0.3% of resistance tests carried out for a previous study in 2019-2021, 5% in samples collected in 2021-22, and 10% in 2023. This mutation seems therefore to be a specific signal of first-time INSTI resistance to either dolutegravir or bictegravir – and may possibly be less damaging if to the latter.
Another interesting fact was that the NRTI mutations of 11 people with INSTI resistance were sequenced too, and not one of them turned out to have the M184V/I resistance mutation to lamivudine / emtricitabine, despite this being the most common NRTI mutation, and despite most of the 11 having other mutations. So far there’s no explanation for this, though M184V is known to lower viral load and could therefore make it harder for HIV to jump over the high resistance barrier to INSTIs.
What comes after dolutegravir?
Finally, if people do experience treatment failure with the second line INSTIs, what treatment options do they have? A study from Dr Ying Zhao of the University of Cape Town looked at people whose second-line protease inhibitor-based regimens had failed – this was usually boosted lopinavir. Of 355 people, 234 had resistance mutations to protease inhibitors. Of these, 133 switched to dolutegravir, compared with 101 who switched to boosted darunavir, regarded as a third-line PI. People who switched to TLD were also compared to another 121 who had failed second-line PIs but did not have PI resistance mutations.
Staying on the old PI did not work well; after 12 months only 35% had suppressed virus, despite not having resistance at baseline, compared with 77% who switched to TLD.
However, switching to boosted darunavir worked just as well as switching to dolutegravir. Eighty-nine per cent and 92% of people on dolutegravir and darunavir respectively maintained viral undetectability at 12 months, despite having PI resistance mutations. This would appear to show potential for boosted darunavir to be a salvage therapy for the still thankfully few people whose second-line INSTI regimens stop working,
References
Van Zyl F Session overview -dolutegravir resistance in resource-limited settings. Conference on Retroviruses and Opportunistic Infections, Denver, themed discussion 11, 2024.
Bello G et al. Emerging dolutegravir resistance among children being investigated for treatment failure in Malawi. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 187, 2024.
Labhardt ND et al. Emerging dolutegravir resistance in Lesotho. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 678, 2024.
Kingwara L et al. DTG resistance with patients with previous ARV experience and viremia in Kenya receiving DTG-based ART. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 677, 2024.
Lessells RJ et al. Viremia and drug resistance two years after routine switching to dolutegravir-based first line ART. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 676, 2024.
Soto-Ramirez LE et al. Resistance to second generation INSTIs in Mexican PLWH: emergence of the R263K mutant. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 679, 2024.
Zhao Y et al. Virologic outcomes with tenofovir-lamivudine-dolutegravir for PI-based second-line ART failure. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 680, 2024.