No difference was observed between the median date of starting the first ENF course of the 2 groups (July 2002 in group A and August 2002 in group B). ENF exposure was 583 (224-1546) days in group A and 543 (462-731) days in group B (P = 0.763). The duration of the first, second, and third ENF course in group B was respectively 294 (211-518), 166 (88-249), and 84 (48-240) days; the median interval between the first and second course was 263 (167-596) days, and that between the second and third course was 211 (63-277) days.
None of the patients in group A received investigational drugs at the time of starting the first ENF cycle, but 1 in group B (5.9%) received tipranavir/ritonavir. During the follow-up, 7 patients in group A (53.8%) were treated with at least 1 investigational drug (4 with darunavir/ritonavir and 3 with tipranavir/ritonavir), and 17 (100%) were in group B. In detail, 7 patients in group B, who did not experience investigational drugs during first cycle, had them added (darunavir/ritonavir, n = 4; tipranavir/ritonavir, n = 2; etravirine, n = 1) during their second ENF course (P = 0.034), and 3 patients had them added (darunavir/ritonavir, n = 1; tipranavir/ritonavir, n = 1; raltegravir, n = 1) during their third course (P = 0.317). Six group B patients, who did not experience investigational drugs previously, had them added after their last ENF cycle.
Considering group B only, CD4 cell counts at the start of the first, second, and third cycle were 54 (17-100), 53 (30-107), and 80 (11-88) cells per milliliter, and HIV RNA levels were 5.22 (5.09-5.53), 5.0 (4.71-5.51), and 4.66 (4.38-4.84) log copies per milliliter. At the end of the first and second cycles, there were significant increases in CD4 counts (P < 0.0001 and P = 0.005) and decreases in HIV RNA levels (P = 0.001 and P = 0.003) but not at the end of the third course (P = 0.156 and P = 0.078) (Table 1).
Six patients in group A (40%) and three in group B (17.7%) died during follow-up (P = 0.243). Death was more likely in patients with a previous AIDS diagnosis (33.3% vs. 12.5%), and this trend was confirmed by the group analyses: 55.6% and 33.3% of the patients who died in group A and B, respectively, had a previous AIDS diagnosis (P = 0.453).
A higher proportion of patients with a previous diagnosis of AIDS developed an AIDS-defining event after starting ENF therapy in group A (n = 5, 50%) than in group B (n = 3, 37.5%), but this difference was not statistically significant (P = 0.664).
A higher survival probability was associated with ENF recycling (P = 0.0006) and an increase of >53 CD4 cells per milliliter (P = 0.003) but not with baseline CD4 (P = 0.973), the presence of a previous AIDS diagnosis (P = 0.277), a decrease in HIV-RNA of >0.5 log10 copies per milliliter at the end of the first course (P = 0.063), or the use of investigational drugs (P = 0.078). The 1-year and 3-year survival rates were 88% and 23% in group A and 100% and 87% in group B (P = 0.0006); 92.7% and 49% for an increase in CD4 cells during the first course of ≤53 cells per milliliter and 100% and 100% for an increase of >53 cells per milliliter (P = 0.008). Survival between groups A and B was also different when considering the increase in CD4 or the decrease in HIV-RNA at the end of the first course (P = 0.003 and P = 0.0003) or the use of investigational drugs (P = 0.003), as shown in Figure 1.
The gp41 genotypes of 6 patients in group B could be determined at each time point; the mutation patterns are shown in Table 3.
We found that the patients who received regimens containing recycled ENF after failing on previous ENF treatment survived significantly longer. This was also observed when the analyses included CD4 gains or HIV-RNA losses at the end of the first course or the use of investigational drugs during follow-up, thus suggesting that the drug had a positive effect on survival. In addition, the duration of first ENF cycle was not related to a different virologic efficacy in the 2 groups and had no effect on survival (data not shown).
All the patients considered in this study had a previous extensive exposure to ARV drugs, and no significant difference in the genotype sensitivity score (GSS) performed at the start of the first ENF cycle was observed between the 2 study groups. Even when stratifying for GSS, significant differences in survival and in immunological and virologic changes persisted between the 2 groups (data not shown). The presence of more than 2 active drugs has been associated with higher virologic success and survival probability10-13; nevertheless, many patients often have no choice but to switch to a new ARV regimen with less than 2 active drugs. Our results suggest that even in these patients, ENF recycling after previous failure to this drug may positively affect survival.
Although multidrug resistance is an independent predictor of mortality,10 similar high survival rates among multidrug-resistant patients starting rescue therapy have been previously described.14 An explanation may be related to the residual activity of the ARVs used.8,15,16 When starting a new rescue regimen with fewer than 3 fully active drugs, the addition of a drug with even limited antiviral activity may have an impact on clinical outcome as it has been shown that immunovirologic17 and clinical benefits can be obtained even under conditions of incomplete viral suppression.18,19
Previous reports have shown that interruption of ENF is followed by a relatively rapid decline in ENF resistance mutations,8,20 which might be due to a mechanism of retromutation rather than the reemergence of wild-type virus.9 Our patients had a long median period without ENF after each cycle, and so it is possible that the virologic activity associated with its reintroduction depends on the ability of the virus to select new resistance mutations, a process that may be slower than the reemergence of archived mutated viral strains, allowing a significant viral decrease in the meantime.
In addition, ENF resistance mutations may have an impact on viral fitness. In vitro data showed an inverse correlation between viral ENF susceptibility and fitness,21 which may be attributed to an impaired fusion efficacy.22 In vivo data are controversial.23,24 We were not able to perform replication capacity assays, but we found that patients who developed resistance mutations during ENF cycles did not have a significant increase in HIV-RNA and lost a lower number of CD4 cells compared with those who did not develop these mutations. These differences were not statistically significant, but the trend suggests a potential impact of reduced viral fitness on the immunovirologic changes we observed during each ENF cycle.
It has been previously reported that immunological recovery may occur even during failure on ENF,8,22,25 and this advantage is often associated with the occurrence of specific mutations such as V38A or V38E.26 In our dataset as well, patients with the V38A/M tended to have longer survival, greater CD4 increase, and virologic decrease than patients without this mutations (data not shown). However, this is not likely to be the only explanation in our case as only 2 patients (33.3%) developed V38A during treatment with ENF and none developed V38E.
We did not find any prevalent mutation in the gp41 genotype during the ENF courses received by the patients in group B. The selection of classic ENF resistance-related mutations was rare, and the type of mutations selected was extremely random. Due to the small number, these findings are difficult to interpret. However, among the mutations selected during the first course, the V38A/M was the only that tended to reemerge during the subsequent courses. These findings are in line with a recent work by Marconi et al23 who showed the persistence of V38A at low levels when ENF is discontinued after failure. Also, they showed that the mutation reemerge quickly if the drug is reintroduced supporting other group's findings suggesting the presence of a pool of independently evolving viral quasispecies in each patient during and after ENF treatment.27 The clinical implications of such findings need to be further clarified in larger studies.
It is known that viral tropism is a predictor of survival28 and that patients harbouring a predominance of X4 or dual/mixed variants29 show faster disease progression. We did not determine viral tropism in our patients, but recent data suggest that an additional effect of ENF on survival may be related to a change in viral tropism from dual/mixed to R5 virus populations, which have been shown to be favoured by ENF treatment in some studies.30,31
The retrospective nature of this study and the limited number of patients makes it difficult to distinguish the effect of ENF from the antiviral response to the investigational drugs, a question that should be addressed in prospective trials.
The availability of new and more convenient oral drugs has meant that many patients have easily achieved undetectable viral levels even in the setting of great multidrug resistance, but a significant proportion still cannot construct a new regimen with 3 active drugs. Given the striking difference in survival found in this study, we suggest ENF recycling after a previous failure should be considered in patients who have similar characteristics with respect to extensive ARVs exposure, GSS, and limited therapeutic options.
We would like thank Alba Bigoloni for assisting the patients with the ENF administration and Andrea Galli for storing the plasma samples and providing laboratory assistance.
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Keywords:Copyright © 2009 Wolters Kluwer Health, Inc. All rights reserved.
AIDS; HIV; enfuvirtide; recycling; resistance; survival