February 6, 2001
Clinical Trials of HIV-1 Protease Inhibitors (Session 41)
Immune Reconstitution (Session 45)
Treatment of Primary Infection (Session 47)
The big story from the antiretroviral therapy (ART) standpoint this week relates to the issuance of the updated DHS guidelines (www.hivatis.org). The revised guidelines recommend more conservative use of potent ART particularly utilizing a CD4+ T-cell count threshold of <350 cells/mm3 as a point when to start treatment. The data presented at this meeting were generally supportive of the new guidelines. No significant results from any large strategy trial were presented so I would not anticipate any major changes in clinical practice as a result of this meeting.
I will focus on information that I learned that provided incremental data on how to better utilize certain drugs already in wide use. Results from the START I and II trials were summarized in a poster presented by Rob Murphy (abstract 314). Those trials compared NRTI backbones of d4T/3TC, d4T/ddI, and ZDV/3TC in combination with indinavir. At the planned analysis of the 48-week data, there was no significant difference between the groups -- though the d4T/3TC arm had the best virologic outcome and the best tolerability -- confirming why that has been a popular combination in practice.
M. Fischl presented the results of ESS40005 (abstract 315) which looked at the comparability of Combivir + Ziagen versus Trizivir. 195 patients on a stable ART regimen (with RNA <400 copies/mL) containing Combivir + Ziagen were randomized to either continue those components (n=98) or switch them to Trizivir (n=97) -- which is the recently approved triple NRTI capsule (taken one capsule twice per day). The week-24 data revealed 92% of the Combivir/Ziagen group maintained RNA levels <400 copies compared to 99% of the Trizivir group. For RNA levels <50 copies/ml, the results were 78% for Combivir/Ziagen and 88% for Trizivir. There were no cases of hypersensitivity reaction in this cohort, not surprising since all the subjects were already taking Ziagen). This study supports the bioequivalence of Combivir/Ziagen and Trizivir.
Dr. Katlama presented the 24-week results of the TRIZAL study (abstract 316) conducted in Europe. Two-hundred and nine patients, on a stable potent ART regimen with plasma RNA <50 copies/mL, were randomized to either continue the same regimen (n=103) or switch to Trizivir (ZDV/3TC, abacavir). At week 24, 17% of the continued HAART group experienced protocol-defined virologic failure versus 20% in the Trizivir group. The rate of possible hypersensitivity reaction in the Trizivir group was 10% (all resolved upon stopping abacavir). There were significant decreases in the cholesterol and triglyceride levels in the Trizivir group compared to the continue group. This study is consistent with other switch studies utilizing abacavir, which have shown comparable potency and improved metabolic parameters.
Two presentations looked at the use of ritonavir-boosted amprenavir (AMP) regimens. R. Wood presented results of a rollover phase of APV2000 (abstract 332). Thirty-six study subjects who had completed a study utilizing standard doses of amprenavir with abacavir and 3TC, elected to switch to a ritonavir-boosted regimen (89% of this cohort had RNA levels <400 copies/mL). Twenty-one subjects switched to AMP 600/RIT 200 BID and 15 switched to AMP 1200/RIT 200 Q day. At 12 weeks, 72% of the BID group and 100% of the Q day group had RNA levels <400 copies/mL. The AMP/RIT regimens were generally well tolerated with increases in cholesterol and triglycerides the major laboratory abnormality (greater in the BID arm). I've experienced good results with the use of AMP/RIT in my own and with patients who particularly appreciate the reduction in the number of amprenavir capsules (sixteen to eight). The 72% rate of virologic success in the BID group at 12 weeks is not particularly reassuring but it is hard to make too much of a small observation study. Marty Markowitz also represented data on his experience with switching 25 study subjects from standard amprenavir dosing to AMP 600mg/RIT 200mg BID (abstract 405). He reported that patients tolerated that regimen better, maintained virologic activity, and had improved pharmacologic parameters compared to the standard dosing for amprenavir. These data provide further support for the increasingly widespread use of amprenavir with ritonavir when amprenavir is utilized as a component of a potent ART regimen.
My last report from this second day of the conference focuses on an important limitation of ART. Although the introduction of potent ART has resulted in significant clinical improvements due to the improved immune status of treated patients, there are limits to the observed immune reconstitution. Hernan Valdez reported on results of T-lymphocyte phenotypic changes observed over a three-year period in patients with moderately advanced HIV disease on effective ART (ACTG 315/375: abstract 372). The bottom line from the study was that the number and function of CD4+ and CD8+ cells does not normalize after three years. The greatest increase in T-cell populations occurred in the first year and the slower increase in subsequent years suggest that the numbers will never reach normal. If HIV-infected patients are to achieve full immune competence (and presumably be more able to handle HIV infection without relying on ART), efforts to boost CD4+ T-cell number and function need to be pursued.