Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

 

Abstract

Background

A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries.

Objectives

To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults.

Search methods

We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status.

Selection criteria

Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults.

Data collection and analysis

Two reviewers independently assessed the methodological quality of the trials and extracted data.

Main results

Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ.

Authors' conclusions

The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

 

Plain language summary

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults

People infected with HIV/AIDS require an antiretroviral regimen that works well, has good activity against the virus, has few adverse effects (unintended negative effects of the drug) and that does not interact with other drugs. The regimen of nevirapine, stavudine and lamivudine is widely used as first-line therapy, and is recommended as such by the World Health Organization for so-called low-resource countries (in other words, for poor countries). This review identified two randomised controlled trials that assessed the efficacy of this drug combination. One trial was a small single-centre Australian trial of 70 participants, whereas the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 participants. In both trials over 60% of participants were male and none had been on previous antiretroviral treatment. As one trial was very small, we cannot be sure of its results. The main findings therefore come from the much larger trial. This trial compared the combination of nevirapine, stavudine and lamivudine with the combination of efavirenz, stavudine and lamivudine, and found that participants had similar treatment outcomes on either combination. It also found that taking nevirapine once a day with twice daily stavudine and lamivudine worked as well as taking nevirapine twice a day in combination with twice daily stavudine and lamivudine. Nevirapine did appear to cause more adverse effects compared with efavirenz, but additional assessment of this is necessary to be more certain.

It is important that more trials which follow participants for a longer time be done to provide better evidence for the use of this combination as a first-line therapy. A trial assessing fixed-drug (providing drugs in a single tablet) is also required, as this reduces the number of pills people must take each day. These studies should include assessment of adverse effects, as well as tracking whether resistance to the drugs develop over time.

 

摘要

背景

Stavudine 、lamivudine 和nevirapine 組合療法作為人類免疫缺乏病毒感染和愛滋病的治療

對於HIV感染及愛滋病病患，一個好的療法要能提供理想的效力、足夠的抗逆轉錄病毒耐受性、可忍受性及少的副作用及藥物交互作用。合併非核甘酸反轉錄酉每抑制劑(NVP)及兩個核甘酸反轉錄酉每抑制劑(stavudine (d4T) and lamivudine (3TC))是目前廣泛應用的第一線療法，特別是在低資源國家。因此對於不管是富有或貧窮國家的臨床工作者、消費者和政府決策人員，分析此種療法的效力、抗病毒耐受性及可忍受性是非常重要的。

目標

評估Stavudine 、lamivudine 和nevirapine 組合療法作為成人人類免疫不全病毒感染和愛滋病的治療效力

搜尋策略

我們運用由Cochrane HIV/AIDS 回顧小組發展的全面檢索策略來辨別HIV/AIDS隨機臨床對照試驗，和搜尋了以下電子資料庫: MEDLINE (2004年7月); Embase (2004年10月); 及CENTRAL(2004年7月)。並且補充AIDSearch(2005年4月)的搜尋資料來辨認相關的會議摘要，並且搜尋所有合格的文章參考目錄。這次的搜尋不受語言及出版刊物的限制。

選擇標準

隨機臨床對照試驗，針對未曾接受過抗逆轉錄病毒療法的成人或已接受過抗逆轉錄病毒療法的成人，比較stavudine、lamivudine和nevirapine的組合療法與所有其他HIV/AIDS療法的治療效果

資料收集與分析

二個評論家獨立地評估試驗的方法品質和提取資料

主要結論

我們的搜尋共產生1,148 個紀錄, 二項研究描述試驗符合我們的納入標準。其中一個試驗為在澳大利亞的小型、單一機構試驗，總計有七十個未曾接受過抗反轉錄病毒療法的參加者。另外一個試驗為大型、多機構試驗，在十四個國家進行，總計有1,216個未曾接受過抗反轉錄病毒療法的參加者。在這兩個臨床試驗中，百分之六十的參加者為男性。由於在兩個臨床試驗中，用來作為對照組的組合療法並不相同，因此無法統合兩個試驗的結果並使用統合分析的方法來加強結果的可性度。因此主要的發現是來自於較大型且品質較好的試驗。從這個試驗發現，比較nevirapine(NVP)或 efavirenz(EFZ)結合3TC與d4T的療法，在療效(由治療失敗來測量)上並無統計學上顯著的意義(相對危險性 = 1.16；百分之九十五信賴區間： 0.95, 1.41)。NVP結合3TC與d4T的療法，比較NVP每日一次的劑量與每日兩次的劑量，在療效上並無統計學上顯著的意義(相對危險性 = 1.00；百分之九十五信賴區間： 0.83, 1.21)。研究同時發現，當比較NVP加上EFZ, 3TC和d4T, 使用每日一次劑量的NVP結合3TC和d4T(相對危險性 = 0.82；百分之九十五信賴區間： 0.67, 1.00)，比使用每日兩次劑量的NVP結合3TC和d4T(相對危險性 = 0.82；百分之九十五信賴區間： 0.69, 0.97)，更能避免治療的失敗。接受NVP的參加者比接受EFZ的參加者有較高的藥物毒性發生率。

作者結論

Nevirapine、3TC和d4T組合療法與efavirenz、3TC和d4T組合療法是一樣有效的。每日一次劑量的NVP合併每日兩次劑量的3TC和d4T與每日兩次劑量的NVP、3TC和4dT比較，是一樣有效的。但是，每日一次劑量的NVP可能有較高的毒性。我們需要更長時間的臨床試驗，來提供足夠的證據，用以證明此種組合療法作為第一線治療的效果。在理想的狀況下，這些臨床試驗要使用標準化的評估方法，尤其是病毒量的測定，如此我們才可以使用統合分析法來結合並比較試驗的結果。

翻譯人

本摘要由臺北榮民總醫院陳炳憲翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

HIV/AIDS感染的患者需要一個好的抗反轉錄病毒療法，這些療法要有好的對抗病毒作用，有較少的副作用 (非預期的藥物負面作用)和不會與其他藥物產生交互作用。Nevirapine, stavudine和lamivudine組合療法被廣泛的應用為第一線治療，並且被世界衛生組織建議使用在低資源國家(貧窮國家)。這篇評論性文章鑑別兩篇隨機臨床對照試驗，並且評估這些藥物組合療法的效果。其中一個試驗為在澳大利亞的小型、單一機構試驗，總計有七十個參加者。另外一個試驗為大型、多機構試驗，在十四個國家進行，總計有1,216個參加者。在這兩個臨床試驗中，百分之六十的參加者為男性並且皆未曾接受過抗反轉錄病毒治療。因為其中一個試驗為小型試驗，我們無法確信它的試驗結果。所以主要的發現都是來自於另一個較大型的試驗。這個試驗比較nevirapine、stavudine、lamivudine組合療法與efavirenz、stavudine、lamivudine組合療法，發現試驗參加者使用兩種組合療法的治療結果是類似的。並且發現使用每日一次劑量的nevirapine合併每日兩次劑量的stavudine、lamivudine與每日兩次劑量的nevirapine、stavudine、lamivudine比較，是一樣有效的。與efavirenz比較，nevirapine似乎造成較多的副作用，但仍需更多的評估來確定。重要的是，在使用此種療法作為第一線治療上，我們仍需要更多的臨床試驗，並且有更長的試驗者追蹤時間，來提供更好的臨床證據。評估固定型藥劑(使用單一藥錠來提供藥物)的臨床試驗也是需要的，因為可以減少病患每日服用的藥錠數量。這些研究需評估包括副作用，並且追蹤這些藥物是否會隨著時間產生抗藥性。