Foli Andrea, Maserati Renato, Barasolo Gabriele, Castelli Francesco, Tomasoni Lina, Migliorino Marco, Maggiolo Franco, Pan Angelo, Paolucci Stefania, Scudeller Luigia, Tinelli Carmine, D'Aquila Richard, Lisziewicz Julianna, Lori Franco
RIGHT at IRCCS Policlinico S Matteo, Pavia, Italy.
Antivir Ther. 2004 Feb;9(1):123-32.
Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured treatment interruptions (STIs) may limit VL rebound, maintain CD4 counts and minimize resistance.
We conducted a clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic HIV infection (CD4 >300, VL >10,000) randomized to receive didanosine-stavudine-indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12 weeks. Subsequently, all patients were randomized again to start STI (short induction) or to continue the therapy for an additional 24 weeks before starting STI (long induction). Both groups underwent four STI cycles and then stopped therapy as long as viraemia remained below 10,000 copies/ml before reinitiating another four cycles of STI.
During continuous therapy VLs were suppressed at similar rates in both the HU and IDV groups, while a blunted CD4 count was documented in the HU group. Following the first stop median VL rebounded close to baseline values in both groups, however, during the following STI median VL rebound decreased in the HU group, while in the IDV group VL continued to rebound to values close to baseline, and the difference between the two groups was statistically significant. Moreover, patients treated with HU had a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in the IDV group, with sharp falls during treatment interruptions and partial CD4 recovery following treatment restart. Even in the presence of IDV resistance predisposing mutations at baseline, no genotypic change in the protease sequence was observed during STI. A relevant mutation in the reverse transcriptase sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of continuous therapy and in one patient after four STI cycles. Side effects (no major events) were similar among groups.
An appropriate choice of STI schedule and regimens containing drugs less prone to resistance and/or able to prevent CD4 fluctuation may contribute to optimizing STI for chronically infected patients with respect to limiting viral rebound, improving CD4 counts and maintaining a resistance profile comparable to continuous highly active antiretroviral therapy.
毒性及其他与药物依从性相关的因素导致HIV感染患者对抗逆转录病毒治疗方案的依从性下降。不规律的治疗中断会导致CD4 T细胞丢失、耐药性产生以及血浆病毒载量（VL）迅速反弹。然而，合理选择药物并适当安排结构化治疗中断（STI），可能会限制VL反弹、维持CD4细胞计数并使耐药性降至最低。
我们开展了一项关于STI的临床研究，即RIGHT 901研究，纳入60例初治的慢性HIV感染患者（CD4＞300，VL＞10,000），随机分为接受去羟肌苷-司他夫定-茚地那韦组（茚地那韦组）或去羟肌苷-司他夫定-羟基脲组（羟基脲组），治疗12周。随后，所有患者再次随机分组，一组开始STI（短期诱导），另一组在开始STI前继续治疗24周（长期诱导）。两组均进行4个STI周期，然后只要病毒血症维持在10,000拷贝/ml以下就停止治疗，之后重新开始另外4个STI周期。
在持续治疗期间，羟基脲组和茚地那韦组的VL抑制率相似，但羟基脲组的CD4细胞计数有所下降。首次停药后，两组的VL中位数均反弹至接近基线值，但在随后的STI期间，羟基脲组的VL中位数反弹有所下降，而茚地那韦组的VL继续反弹至接近基线值，两组之间的差异具有统计学意义。此外，接受羟基脲治疗的患者在STI期间CD4细胞持续稳定增加，而茚地那韦组的CD4细胞计数波动较大，在治疗中断期间急剧下降，治疗重新开始后部分CD4细胞恢复。即使在基线时存在茚地那韦耐药性相关突变，在STI期间蛋白酶序列也未观察到基因型变化。在一名连续治疗36周后中断治疗的患者以及一名经过4个STI周期后的患者中，逆转录酶序列出现了一个相关突变（K70R）。各组间的副作用（无重大事件）相似。
适当选择STI方案以及使用不易产生耐药性和/或能够防止CD4细胞计数波动的药物，可能有助于为慢性感染患者优化STI，从而限制病毒反弹、提高CD4细胞计数并维持与持续高效抗逆转录病毒治疗相当的耐药情况。
