(dolutegravir / lamivudine)的治療基斯‧奧爾康 / 2024 年 5 月 7 日 / aidsmap
一項針對在義大利和法國診所愛滋病毒感染者簡化治療的研究得出結論，在改用多替拉韋/拉米夫定（Dovato）後，隱藏的B型肝炎感染可能會破壞病毒抑制。
研究人員建議對任何具有隱性B型肝炎感染標記的人，針對其B型肝炎活動和愛滋病毒抑制進行仔細監測，亦即其B型肝炎核心抗原抗體，並沒有相對應於B型肝炎表面抗原抗體。
對於B型肝炎表面抗原陽性（活動性B型肝炎感染）的患者，不建議從含有替諾福韋(tenofovir) 的治療方案轉換為核苷保留治療 (nucleoside-sparing treatment)或含有拉米夫定的雙重治療。 這是因為愛滋病毒感染者可能會經歷B型肝炎重新活化和B型肝炎複製加劇，導致嚴重的肝損傷。 儘管拉米夫定對B型肝炎具有活性，但對該藥物的抗藥性可能會迅速出現。
當肝組織或血液中檢測到B型肝炎 DNA，但不存在B型肝炎表面抗原 (HBsAg) 或表面抗原抗體時，人們可能患有「隱性」或隱藏的B型肝炎感染。 接觸過B型肝炎並隨後清除感染的人存留了B型肝炎核心抗原 (HBcAg) 的抗體，而 B型肝炎核心抗原的抗體也可能是新感染的跡象。 隱匿性B型肝炎的影響尚不確定； 那些針對隱匿性B型肝炎患者肝病的研究呈現了相互矛盾的結果。
隱匿性B型肝炎的盛行率因地區而異，在B型肝炎傳播較常見的地區，隱匿性B型肝炎的盛行率似乎較高。 非洲愛滋病毒感染者的盛行率研究進行的統合分析顯示，隱性感染的總體盛行率為 11%，但在南部非洲則上升至 26%。 義大利的一項研究發現，在擁有B型肝炎核心抗原抗體的愛滋病毒感染者中，有30% 的人會有低水平的B型肝炎複製，而另一項研究發現，擁有B型肝炎核心抗原抗體與抗反轉錄病毒治療的病毒學控制較差相關。
目前的歐洲指南稱，具有B型肝炎核心抗原抗體的人在改用多替拉韋/拉米夫定後應進行監測，但不建議該群體使用該組合。
義大利研究人員擔心，如果人們從多替拉韋/拉米夫定的三種藥物治療方案轉為兩種藥物治療，由於對B型肝炎的抑制效果較差，如果他們轉為兩種藥物治療，可能會出現病毒學控制較差的風險。他們與巴黎聖安東尼醫院的 Karine Lacombe 進行了一項回顧性多中心研究來調查這個問題。
研究族群包括 267 名參與診所的 HIV 感染者，從三種藥物治療轉為多替拉韋/拉米夫定，並且在轉用和追蹤數據時病毒量低於 50 拷貝/毫升。 百分之二十八的人有B型肝炎核心抗原的抗體，且在這些人當中有四分之三的人有B型肝炎表面抗原的抗體。
參與者的平均年齡為 41 歲，其中 32% 為女性。 在轉換之前，46% 的人服用兩種核苷反轉錄酶抑制劑(NRTI) 和一種整合酶抑制劑，33% 的人服用兩種NRTI 和一種非核苷反轉錄酶抑制劑，15%的人服用蛋白酶抑制劑和兩種NRTI。 轉換時 CD4 計數中位數為 754。
該研究檢視了從轉換前 24 個月到轉換後 36 個月期間病毒量的變化。
大多數參與者 (74%) 有長期病毒量抑制史（至少兩年低於 20 拷貝/毫升，且未檢測到目標，顯示沒有檢測到任何病毒）。 在轉換時，85% 的病毒量低於20 拷貝且未檢測到目標，略低於10% 的病毒量低於20 拷貝/毫升但檢測到目標（顯示可檢測到病毒，但低於20 拷貝），其餘的人則病毒量在20 拷貝到 50 拷貝/ml 之間。
在轉換後6 個月和12 個月時，82% 的病毒量低於20 拷貝/ml，且未檢測到目標；而分別有8% 和9% 的病毒量低於20 拷貝/ml，但偵測到目標。在第 6 個月時，有8% 的病毒量在 20 拷貝/毫升到 50 拷貝/毫升之間。 但到了第 12 個月，有5% 的病毒量在 20 拷貝/毫升到 50 拷貝/毫升之間，有3% 的病毒量高於 50 拷貝/毫升但低於 200 拷貝/毫升。
在轉換後24 和36 個月時，84% 的病毒量低於20 拷貝/毫升，且未檢測到目標；而分別有9% 和12% 的病毒量低於20 拷貝/毫升，但檢測到目標。 在第 24 個月時，4% 的病毒量在 20 拷貝/毫升至 50 拷貝/毫升之間。但到了第 36 個月，2% 的病毒量在 20 到 50 拷貝/毫升之間，2% 的病毒量超過 50拷貝數但低於 200 拷貝/ml。 在第 36 個月時，3% 的病毒量在 20 拷貝/ml 至 50 拷貝/ml 之間，不到 1% 的病毒量高於 50 拷貝/ml 但低於 200 拷貝/ml。
這些數字掩蓋了病毒可檢測性的某種程度上之波動。 在追蹤 36 個月中，只有一半的參與者係保持病毒量低於 20 個拷貝，且未檢測到目標，這顯示其在追蹤期間所有測量點均實現了病毒完全抑制。
在轉換之前，具有B型肝炎核心抗原抗體的人和沒有B型肝炎核心抗原抗體的人之間的病毒抑制沒有差異。 但從轉換後 12 個月開始，具有B型肝炎核心抗原抗體的人中，其病毒量低於 20 個拷貝且未檢測到目標的比例較低（69% vs 87%，p=0.004）。 他們更有可能在病毒量低於 20 個拷貝，以及病毒量在 20 至 50 個拷貝/ml 之間時檢測到目標。 同樣的模式在隨後的時間點也成立，因此，到第36 個月時，有26% 的具有B型肝炎核心抗原抗體的人，他的病毒載量低於20 個拷貝但卻檢測到目標，而卻只有18% 的人在各個偵測時間點保持病毒量低於20 個拷貝且未偵測到目標。
「低水平的B型肝炎複製可能會刺激愛滋病毒複製，從而增加病毒反彈的風險」。
一項考慮了年齡、感染HIV 年份、CD4 計數、病毒學失敗史和B型肝炎核心抗原狀態的多變量分析顯示，具有B型肝炎核心抗原抗體的人在第36 個月時可檢測到HIV 的可能性為三倍，這是與病毒可檢測性顯著相關的唯一因素（p=0.005）。
研究人員推測，低水平的B型肝炎複製可能會刺激愛滋病毒複製，最終增加服用多替拉韋/拉米夫定的人病毒反彈的風險。 當攜帶B型肝炎核心抗原抗體的人改用替諾福韋保留方案（包括不含抑制B型肝炎藥物的長效方案）時，就需要考慮到這種風險。
然而，研究人員承認，由於大多數診所沒有定期測量具有B型肝炎核心抗原抗體的人群中的B型肝炎DNA，因此他們不知道在轉換時已經檢測到HBV DNA 的參與者比例是多少，或者在追蹤期間有多少比例發展為可檢測到的 HBV DNA ，以及其與不完全 HIV 抑制的出現有何關係。
他們得出結論，我們需要的是一項前瞻性研究，監測簡化治療和停止替諾福韋治療前後的B型肝炎 DNA 水平。 他們建議，一項研究還應該調查具有B型肝炎核心抗原抗體的人的B型肝炎疫苗接種反應是否對轉換後的愛滋病毒或B型肝炎病毒檢測有影響。
參考文獻：
Malagnino V et al. HBcAb 陽性是 3TC+DTG 轉換後 HIV RNA 缺失的危險因子。 《病毒》，線上發布，2024 年 2 月 23 日。
Hidden hepatitis B infection may compromise dolutegravir / lamivudine treatment
Keith Alcorn / 7 May 2024 / aidsmap
Having a hidden infection with hepatitis B may undermine viral suppression after a switch to dolutegravir / lamivudine (Dovato), a study of people with HIV who simplified treatment in Italian and French clinics has concluded.
The study investigators recommend careful monitoring of hepatitis B activity and HIV suppression in anyone with markers suggesting a hidden hepatitis B infection – antibodies to hepatitis B core antigen without corresponding antibodies to the hepatitis B surface antigen.
A switch from a regimen that contains tenofovir to nucleoside-sparing treatment or dual therapy containing lamivudine is not recommended for people who are positive for hepatitis B surface antigen (active hepatitis B infection). This is because people with HIV may experience hepatitis B reactivation and flares in hepatitis B replication that can lead to severe liver damage. Although lamivudine is active against hepatitis B, resistance to the drug can emerge rapidly.
People can have an ‘occult’ or hidden hepatitis B infection when hepatitis B DNA is detectable in liver tissue or blood without the presence of hepatitis B surface antigen (HBsAg) or antibodies to surface antigen. People exposed to hepatitis B who subsequently clear the infection retain antibodies to hepatitis B core antigen (HBcAg). Antibodies to hepatitis B core antigen can also be a sign of a new infection. The implications of occult hepatitis B are uncertain; those studies that have looked at liver disease in people with occult hepatitis B have reported contradictory findings.
The prevalence of occult hepatitis B varies between regions and appears higher where hepatitis B transmission is more common. A meta-analysis of prevalence studies carried out in people with HIV in Africa showed an overall prevalence of occult infection of 11%, rising to 26% in southern Africa. And one Italian study found that 30% of people with HIV who had antibodies to hepatitis B core antigen had very low-level hepatitis B replication, while another found that having antibodies to hepatitis B core antigen was correlated with poorer virological control on antiretroviral treatment.
Current European guidelines say that people with antibodies to hepatitis B core antigen should be monitored after switching to dolutegravir / lamivudine but do not advise against the use of the combination for this group.
Italian researchers were concerned by the risk that people switching from a three-drug regimen to two-drug treatment with dolutegravir / lamivudine might experience poorer virological control if they switched to two-drug treatment, due to less effective suppression of hepatitis B. They carried out a retrospective multicentre study with Karine Lacombe at the Hôpital Saint Antoine in Paris to investigate the issue.
The study population consisted of 267 people with HIV at participating clinics who had switched from three-drug treatment to dolutegravir / lamivudine and who had a viral load below 50 copies/ml at the time of switching and follow-up data. Twenty-eight percent had antibodies to hepatitis B core antigen and of these, three-quarters had antibodies to hepatitis B surface antigen.
Participants had a median age of 41 years and 32% were female. Before switching, 46% were taking two nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase inhibitor, 33% two NRTIs and a non-nucleoside reverse transcriptase inhibitor and 15% a protease inhibitor with two NRTIs. The median CD4 count at the time of switching was 754.
The study examined changes in viral load from 24 months before switching until 36 months after switching.
Most participants (74%) had a history of prolonged viral load suppression (at least two years below 20 copies/ml and target not detected, indicating no detectable virus whatsoever). At the time of switching, 85% had viral load below 20 copies and target not detected, just under 10% had viral load below 20 copies/ml but target detected (indicating detectable virus but below 20 copies), and the remainder had viral loads between 20 copies and 50 copies/ml.
At six and 12 months after switching, 82% had viral load below 20 copies/ml and target not detected, while 8% and 9% respectively had viral load below 20 copies/ml but target detected. At month 6, 8% had viral load between 20 copies and 50 copies/ml. By month 12, 5% had viral load between 20 copies and 50 copies/ml and 3% had viral load above 50 copies but below 200 copies/ml.
At 24 and 36 months after switching, 84% had viral load below 20 copies/ml and target not detected, while 9% and 12% respectively had viral load below 20 copies/ml but target detected. At month 24, 4% had viral load between 20 copies and 50 copies/ml. By month 36, 2% had viral load between 20 copies and 50 copies/ml and 2% had viral load above 50 copies but below 200 copies/ml. At month 36, 3% had viral load between 20 copies and 50 copies/ml and less than 1% had viral load above 50 copies but below 200 copies/ml.
These figures disguise a degree of fluctuation in viral detectability. Only half of participants followed for 36 months maintained a viral load below 20 copies with target not detected, indicating complete viral suppression at all measurement points during the follow-up period.
Before switching, there was no difference in viral suppression between people who had antibodies to hepatitis B core antigen and those who did not. But from 12 months after switching, a lower proportion of those with antibodies to hepatitis B core antigen had viral load below 20 copies with target not detected (69% vs 87%, p=0.004). They were more likely to have target detected viral load measurements below 20 copies and to have viral loads between 20 and 50 copies/ml. The same pattern held true at subsequent time points, so that, by month 36, 26% of those with antibodies to hepatitis B core antigen had viral load below 20 copies with target detected and only 18% had maintained a viral load below 20 copies with target not detected at all time points.
“Low-level hepatitis B replication could be stimulating HIV replication, raising the risk of viral rebound.”
A multivariable analysis that considered age, year of HIV acquisition, CD4 count, history of virological failure and hepatitis B core antigen status showed that people with antibody to hepatitis B core antigen were three times more likely to have detectable HIV at month 36 and this was the only factor significantly associated with viral detectability (p=0.005).
The study investigators speculate that low-level hepatitis B replication could be stimulating HIV replication, eventually raising the risk of viral rebound in people taking dolutegravir / lamivudine. This risk needs to be taken into account when people with antibodies to hepatitis B core antigen switch to tenofovir-sparing regimens, including long-acting regimens that do not contain agents that suppress hepatitis B.
However, the study investigators acknowledge that because most clinics did not measure hepatitis B DNA routinely in people with antibodies to hepatitis B core antigen, they do not know what proportion of participants already had detectable HBV DNA at the time of switching – or what proportion developed detectable HBV DNA during follow-up and how that correlated with the emergence of incomplete HIV suppression.
What’s needed, they conclude, is a prospective study which monitors hepatitis B DNA levels before and after treatment simplification and discontinuation of tenofovir-based treatment. A study should also investigate whether hepatitis B vaccination response in people with antibodies to hepatitis B core antigen has any impact on HIV or HBV viral detectability after switching, they suggest.
References
Malagnino V et al. HBcAb positivity as a risk factor for missing HIV RNA undetectability after the 3TC+DTG switch. Viruses, published online, 23 February 2024.