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No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients
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AIDS: Volume 19(15) 14 October 2005 p 1643-1647
Ghosn, Jadea,d; Wirden, Marcb; Ktorza, Nadinea; Peytavin, Gillesc; Aït-Mohand, Hocinea,d; Schneider, Luminitaa,d; Dominguez, Stephaniea,d; Bricaire, Françoisa; Calvez, Vincentb; Costagliola, Dominiqued; Katlama, Christinea,d
From the aDepartment of Infectious and Tropical Diseases
bVirology Laboratory, Hospital Pitie-Salpetriere
cToxicology Laboratory and Pharmacology Clinic, Hospital Bichat-Claude Bernard
dINSERM EMI 0214, Pierre et Marie Curie University, Paris, France.
"....This study shows that, in patients with multiple treatment failure, prolonged treatment interruption adds no virological benefit, despite an initial reversion to a nearly wild-type virus....prolonged treatment interruption in patients with CD4 cell counts < 200 cells was clinically deleterious.....a median seven-drug salvage regimen was not able to achieve a 1 log copies/ml reduction in viral load except in one patient.....the rapid reemergence after treatment resumption of the resistant variants with the same mutational pattern as at baseline suggests that those resistant variants had not disappeared but had simply been out-competed by wild-type strains during treatment interruption.....The median CD4 cell count in the seven patients who experienced major AIDS-defining events did not differ significantly between baseline (6 cells) and the event (4 cells). Furthermore, prolonged treatment interruption led only to a small increase (0.54 log copies/ml) in viral load from baseline....one can hypothesize that progression of HIV disease was most likely related to the greater fitness of the reverted strains after treatment interruption, as previously shown by Deeks et al. [8], and/or a different impact on the immune system of wild-type virus compared with the highly mutated virus at baseline....."
See EDITORIAL at the bottom of this report:
Authors say: ".....Certainly, the negative clinical results and the lack of virological and immunological benefit that comprehensively emerges from clinical studies of structured treatment interruption should advise against the use of this strategy in patients with advanced disease, multiple failed regimens, low CD4 cell count and previous experience of AIDS-related events...."
Presented in part at the Ninth EACS Conference, October 2003, Warsaw, Poland [abstract F7/5].
BACKGROUND
Despite the success of highly active antiretroviral therapy (HAART) [1], viral resistance remains problematic [2-4]. Severe treatment failure, defined as a CD4 cell count < 200 x 106 cells/l and plasma HIV RNA load > 30 000 copies/ml, affects 5% of patients enrolled in the French hospital HIV database [5]. Treatment options for such patients are often extremely limited, owing to broad intraclass drug cross-resistance [6] and limited access to new drugs. It has been shown that treatment interruption allowed reemergence of archived wild-type virus that out-competes the less-fit resistant strains [7,8]. However, although this may lead to an improved virological response on treatment resumption [9], the wild-type virus may have an increased capacity to replicate and, therefore, to delete peripheral blood CD4 cells [8]. Conflicting results have been obtained in this clinical setting [10-15]. We recently reported that an 8-week treatment interruption in the GigHAART study was beneficial for treatment-experienced patients with multidrug-resistant virus on resuming a salvage regimen [12]. As reversion of resistance mutations in plasma increases with the duration of treatment interruption [16,17], the present study examined the possible benefits of prolonged treatment interruption based on genotypic resistance testing (GRT), followed by optimized salvage gigatherapy in heavily pretreated HIV-infected patients with multidrug-resistant viruses.
ABSTRACT
Objective: To evaluate the potential benefits of a tailored antiretroviral treatment interruption with duration based on the observed reversion of resistance mutations.
Methods: In this open single-arm pilot study, 23 patients with multiple treatment failure interrupted therapy and underwent longitudinal genotypic resistance testing. Salvage gigatherapy was started when resistance mutations to at least two antiretroviral drug classes reverted. The primary endpoint was a fall in viral load by > 1 log10 copies/ml after 12 weeks of salvage therapy.
Results: Baseline median viral load was 5.14 log copies/ml and CD4 cell count 43 x 106 cells/l. Genotypic resistance testing showed a median of six, two and nine resistance mutations to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors, respectively; viral strains were susceptible to no more than one drug in 17/23 patients. The median duration of treatment interruption was 24 weeks (range, 12-37), leading to median changes from baseline of + 0.54 log10 copies/ml and -30 x 106 cells/l (range: -252 to +6). At the end of treatment interruption, plasma HIV was susceptible to at least three drugs in 16/23 patients. After 12 weeks of salvage multitherapy, only one patient had a decrease in viral load > 1 log copies/ml. All baseline resistance mutations recurred after treatment resumption. AIDS-defining events occurred in two-thirds of patients during the study period.
Conclusion: In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged treatment interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious.
Methods
Study design
The Reverse study was an open, single-arm study in which the length of treatment interruption was based on the observed reversion of resistance mutations; the endpoint was the virological efficacy of a salvage regimen. The failing regimen was discontinued for at least 8 weeks, and GRT was monitored. A salvage regimen was restarted when resistance mutations to at least two antiretroviral classes had reverted, as follows: loss of at least three thymidine-associated resistance mutations (TAM), loss of all mutations associated with resistance to non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), loss of at least three primary mutations associated with resistance to protease inhibitors (PI). Salvage therapy was restarted at any time if an AIDS-related event occurred or after a maximum of 26 weeks even if reversion criteria were not met.
Patients
Patients were eligible if they had plasma HIV-1 RNA > 30 000 copies/ml despite treatment with three or more antiretroviral drugs. Genotypic viral resistance had to include at least three TAM, plus one NNRTI resistance-associated mutation and two primary PI resistance-associated mutations. All the patients gave their written informed consent.
Study treatment
The salvage regimen consisted of six to eight antiretroviral drugs per patient, comprising three to four NRTI, one NNRTI and two or three ritonavir-boosted PI, optimized according to GRT results and patient treatment history.
Clinical and laboratory evaluations
Patients were screened within 4 weeks of enrollment (day 0), then after 2, 4 and 8 weeks of treatment interruption (TI-W2, TI-W4, TI-W8) and every 6 weeks thereafter until resumption of salvage therapy (R-W0). They were then examined every 4 weeks for 24 weeks (to R-W24). Plasma HIV RNA was quantified using the Amplicor Monitor assay 1.5 (Roche Diagnostics, Meylan, France) with a detection limit of 400 copies/ml. GRT (population-based full sequence analysis) was performed on plasma HIV-1 RNA as previously described [18,19] and interpreted using the ANRS AC11 algorithm ( http://www.HIVfrenchresistance.org/ ). A genotypic susceptibility score (GSS) [20] was calculated as the total number of active antiretroviral drugs among a panel of NRTI, NNRTI and PI according to the post-treatment interruption regimen prescribed.
Antiretroviral drug assays
Steady-state drug concentrations were measured at weeks 2 and 12 of salvage therapy. Minimal effective plasma trough concentrations were those used in the GigHAART study [12]. Concentrations were considered adequate at a given time-point if all but one drug trough concentration were above the cut-off at both visits.
Study endpoints
The primary endpoint of the study was the percentage of patients with a decrease in viral load (viral load) of 1 log10 copies/ml HIV RNA at 12 weeks after treatment resumption (R-W12), relative to the baseline. Secondary endpoints were the changes in CD4 cell count, the evolution of plasma viral load after 12 and 24 weeks of salvage therapy (R-W12, R-W24) and the proportion of patients experiencing AIDS-defining events.
Statistical analysis
The number of subjects enrolled in the study (23) was sufficient to estimate a treatment success rate equal to that observed (60%) in the GigHAART study [12], with a precision of ± 20%. Changes in continuous variables were tested for significance using Wilcoxon's paired test.
RESULTS
Characteristics of the patients
A total of 23 patients were enrolled in the study from June 2001 to March 2002. Patients had all received substantial treatment for HIV with a median duration of treatment of 8.5 years (range, 4.5-13.2) and with a median of 13 antiretroviral drugs (range, 11-16). Thirteen patients (57%) had a history of AIDS-defining event(s). At baseline, the median plasma viral load was 5.14 log copies/ml (range, 4.51-5.69), and the median CD4 cell count 43 x 106 cells/l (range, 1-372). The baseline median number of resistance mutations to the three classes of drug was 17 (range, 9-28), with a median of six NRTI-associated mutations (range, 4-11) including four TAM (range, 3-6), two NNRTI-associated mutations (range, 1-3) and nine PI-associated mutations (range, 4-14). Overall, the mean global GSS for NRTI, NNRTI and PI was 0.8 ± 1.1. Ten patients (44%) had HIV strains susceptible to no drugs and seven patients (30%) had HIV strains susceptible to only one drug.
Treatment interruption
The median duration of treatment interruption was 24 weeks (range, 12-37).
Plasma viral load increased by a median of 0.53 log copies/ml (range -0.17 to + 1.54) and the CD4 cell count fell by a median of 30 x 106 cells/l (range, -252 to + 6) from baseline.
At the end of treatment interruption, GRT showed a significant reversion of resistance mutations to wild-type amino acid residues. Sixteen patients (70%) met reversion criteria at salvage therapy resumption, a shift to a complete wild-type virus occurring in five patients (22%). Overall, the mean total GSS at treatment resumption was 4.9 ± 2.8, with a significant increase of 4 from baseline (P < 0.001). At the end of the treatment interruption, 16 patients (70%) had plasma HIV susceptible to at least three antiretroviral drugs.
Salvage therapy
Salvage therapy comprised a median of seven drugs (range, 4-8) with all 23 patients taking lamivudine; other drugs were abacavir and tenofovir (19), didanosine (18), efavirenz (12), nevirapine (7), delavirdine (1), ritonavir (23), lopinavir (17), indinavir (13), saquinavir (11), and amprenavir (9). Only three patients received fewer than six drugs because of multiple drug intolerance. In 70%, at least three drugs that were prescribed within the salvage regimen were classified as active after treatment interruption according to GRT. All patients had adequate plasma drug concentrations at R-W2 and R-W12 (data not shown).
By intent-to-treat analysis, only one patient achieved a 1 log copies/ml decline in viral load after 12 weeks of salvage therapy. Overall, the median change from baseline was + 0.04 log copies/ml (range, -1.06 to + 0.58) in plasma HIV RNA and -27 x 106 cells/l (range, -189 to + 44) in CD4 cell count. Results were similar at 24 weeks. All resistance mutations present at baseline recurred 4 weeks after resuming treatment in 13 patients and by 24 weeks in the 10 remaining patients.
Clinical outcome
An AIDS-defining event was seen in 15 (65%) of the 23 patients, including oesophageal candidiasis (eight), lymphoma (one), pulmonary Kaposi's sarcoma (one), Pneumocystis carinii pneumonia (one), multiple progressive leucoencephalopathy (one), disseminated Mycobacterium avium intracellulare infection (one), AIDS-related wasting syndrome (two) and cytomegalovirus colitis (one). Four of these patients experienced more than one AIDS-defining event. All these events occurred between R-W0 and R-W24. There was no significant difference in the CD4 cell count, at baseline (P = 0.548) or at the end of treatment interruption (P = 0.585), between the 15 patients who had AIDS-defining events (baseline: 36 x 106 cells/l; end of treatment interruption: 12 x 106 cells/l) and the eight who did not have AIDS-defining events (baseline: 76 x 106 cells/l; end of treatment interruption: 27 x 106 cells/l).
The seven patients who experienced a major AIDS-related event (all events listed above except oesophageal candidiasis) had a baseline CD4 cell count of 6 x 106 cells/l, compared with 76 x 106 cells/l in the other 16 patients (P = 0.065). However, in these seven patients, the CD4 cell count at the time of AIDS-related event (median 4 x 106 cells/l) was similar to that at baseline (median 6 x 106 cells/l), suggesting that the progression of HIV disease could not be related to a significant decrease in CD4 cell count.
AUTHOR DISCUSSION
Discussion TOP
This study shows that, in patients with multiple treatment failure, prolonged treatment interruption adds no virological benefit, despite an initial reversion to a nearly wild-type virus. Indeed, these patients harboured multidrug-resistant viruses at baseline, with a GSS of < 1. Treatment interruption led to a significant decrease in the burden of resistance mutations, improving the GSS of plasma HIV from 0.9 to 4.9 active drugs at the end of treatment interruption (P < 0.001). Two-thirds of the patients received a salvage regimen containing at least three drugs to which their plasma HIV dominant variant had become susceptible after treatment interruption, and plasma drug concentrations were adequate. However, despite this improvement in HIV drug sensitivity, a median seven-drug salvage regimen was not able to achieve a 1 log copies/ml reduction in viral load except in one patient. This strongly contrasts with the results observed in the GigHAART study, in which viral load fell by 1.91 log copies/ml in the group with an 8-week treatment interruption [12]. It seems that the key issue in the efficacy of a salvage regimen is the number of drugs retaining potential viral activity before any intervention. Indeed, in GigHAART, baseline GSS was 1.4, meaning that, in most patients, one drug was still genotypically active, mainly lopinavir or amprenavir at that time (1998-1999). In our Reverse study, baseline GSS was < 1, with no available new active antiretroviral drugs to which the patients had not been exposed. The improvement in GSS after a median 24-week-treatment interruption in our Reverse study did not restore the antiviral efficacy of a multiple salvage regimen that comprised recycled drugs. Furthermore, the rapid reemergence after treatment resumption of the resistant variants with the same mutational pattern as at baseline suggests that those resistant variants had not disappeared [21,22] but had simply been out-competed by wild-type strains during treatment interruption.
We observed a high rate of HIV-related events (15/23 patients, 65%). Of note, these events occurred after the end of treatment interruption. Interestingly, the slope of CD4 cell count change did not alter in a major way in any of the 23 patients in the 6 months prior to inclusion, despite a median viral load > 5 log copies/ml. The median CD4 cell count in the seven patients who experienced major AIDS-defining events did not differ significantly between baseline (6 x 106 cells/l) and the event (4 x 106 cells/l). Furthermore, prolonged treatment interruption led only to a small increase (0.54 log copies/ml) in viral load from baseline. The studies CPCRA 064 [10] and ACTG 5086 [13], which both involved a 16-week treatment interruption, also showed deleterious clinical consequences despite significant reversion of resistance mutations. Cohort studies have also suggested that treatment interruption had a negative impact on the prognosis for heavily pretreated patients [23,24]. In Reverse, prolonged treatment interruption led neither to a significant fall in CD4 cell count in patients experiencing major AIDS-events nor to a significant increase in viral load; therefore, one can hypothesize that progression of HIV disease was most likely related to the greater fitness of the reverted strains after treatment interruption, as previously shown by Deeks et al. [8], and/or a different impact on the immune system of wild-type virus compared with the highly mutated virus at baseline. This is supported by the GigHAART results, where an 8-week treatment interruption in very severely immunocompromised patients induced few reversions of resistance mutations and no increase in clinical events.
In conclusion, significant reversion of resistance mutations in plasma HIV strains did not yield any virological benefit for patients with multiple resistant virus at baseline in the absence of any possibility of adding new potent drugs to the regimen. Furthermore, in our experience, prolonged treatment interruption in patients with CD4 cell counts < 200 x 106 cells/l was clinically deleterious. However, whether short-term treatment interruption would restore the antiviral efficacy of a subsequent salvage gigatherapy with several potent drugs to which the patient has not yet been exposed (including drugs still under investigation in 2004, e.g., tipranavir, TMC 114) and new classes of drug with no cross-resistance to the previously failing treatment) warrants further evaluation.
EDITORIAL
AIDS: Volume 19(15) 14 October 2005 p 1691-1694
Structured treatment interruption in HIV-infected patients failing on multidrug therapy: is there a future for this strategy?
Antinori, Andreaa; Cingolani, Antonellab; Perno, Carlo Federicoa
From the aNational Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS
bDepartment of Infectious Diseases, Catholic University, Rome, Italy.
Among factors that might limit the benefits of highly active antiretroviral therapy (HAART), other than suboptimal medication adherence and drug toxicities, most concern centred on the development of resistant viral variants, which can compromise the virological response rate of treatment regimens [1]. Large surveys of HAART-experienced populations have shown that the probability of developing a multiclass drug resistance is approximately 20-42% after several years of treatment [2,3]. Therefore, interest has grown in developing new strategies for patients with few or no therapeutic options because of the presence of multidrug-resistant viral strains [4].
One of the critical points under discussion is whether complete viral suppression represents the preferred end-point of clinical strategy in this late phase of the natural history of treatment. Several observations suggest that drug-resistant HIV-1 has differing degrees of decreased replicative capacity [5] compared with wild-type virus. Consequently, discontinuation of antiretroviral therapy in patients with multidrug-resistant virus may rapidly cause overgrowth by wild-type virus, with a hypothetical decline of resistance and reversion of genotypic mutations [6-8]. However, maintaining a failed regimen to which HIV is resistant may still keep viral replicative capacity low, and so the likelihood of immunological deterioration and clinic progression could be reduced [9]. Stopping antiretroviral therapy in order to modify the HIV-resistance profile from multidrug resistance to a more sensitive pattern, ideally to wild type, might be expected to improve the chances of obtaining durable virological suppression and immunological benefit after reintroduction of therapy. In chronic HIV infection, amongst patients experiencing virological failure, treatment interruption could be considered a valid strategy alternative to the maintenance of an ineffective, and often complicated, regimen that carries the risk of resistance-mutation evolution and cumulative drug toxicities.
Unfortunately, theoretical hypotheses in this field are not yet supported by observations from clinical practice. However, the hypothesis that treatment interruption could provide an opportunity for durable viral suppression and consistent clinical benefit has been tested in some clinical studies [7,8,10-13] (Table 1). After preliminary uncontrolled virological studies [7,8], several randomized approaches have been developed. The Retrogene study used 12 weeks of interruption and a five-drug standardized rescue regimen at reintroduction; no difference in terms of virological and immunological benefit was observed at 48 weeks in patients who had interrupted therapy compared with those who had no interruption [10]. Similarly, in CPCRA 064, with 16 weeks of interruption and a genotype- and phenotype-based salvage therapy, no different in plasma viral load was detected after 12 weeks, but there was a more than two-fold increased risk of clinical progression or death in the treatment interruption group [11]. By comparison, a better virological and immunological response was observed in the interruption arm in ANRS 097, a randomized study of patients with very advanced multidrug resistance. In this study, a shorter (8 weeks) treatment interruption was followed by a salvage regimen with multiple drugs (mean of more than seven) [12]. Differences among the three trials for design and study characteristics may have contributed to the substantially different results obtained.
In the present issue of AIDS, Ghosn et al. [13] have reported the results of an open-label non-randomized study of 23 patients with advanced HIV infection and multiple treatment failure; these patients interrupted their antiretroviral treatment for at least 8 weeks and until resistance in at least two antiretroviral drug classes had reverted to wild type as assessed by genotypic monitoring. After a median of interruption of 24 weeks and 12 weeks of multidrug rescue therapy (median seven drugs), median changes from baseline were +0.04 log10 copies/ml for viral HIV RNA and -27 x 106 cells/l (from a median baseline value of 43 x 106 cells/l) for CD4 cell count. Further, 65% of the enrolled patients experienced an AIDS-defining event.
Surprisingly, these results were substantially different from those observed by the same group in the ANRS 097 trial, despite similar baseline characteristics: CD4 cell count as low and an equivalent number of antiretroviral drugs in the rescue regimens [12,13]. Moreover, an unexpected difference in virological response was obtained in the two studies despite an even more complete reversion of genotypic mutations in the Reverse study (70% vs 52%) achieved by its more prolonged interruption period. Ghosn et al. [13] explained the higher failure rate of the Reverse study compared with ANRS 097 by the contribution of newly available drugs to the success of rescue regimens in the latter study, an option that was not available in the Reverse study. Remarkably, in the Reverse study, the baseline genotypic sensitivity score, which could be considered a measure of residual antiretroviral activity in patients failing on multidrug therapy, was < 1, whereas in the ANRS 097 it was 1.4, because of the residual activity of lopinavir and amprenavir at the time of the study [12]. Failure to achieve reduction in virus load in the Reverse study [13], despite the significant increase of genotypic sensitivity score from baseline achieved by the treatment interruption, suggests that the improvement of genotypic sensitivity score may not invariably reflect the antiviral efficacy of recycled drugs. The quite frequent reemergence of mutated strains after reversion, as previously reported [5,14], is consistent with the hypothesis that the resistant virus might persist as a minority population even in the presence of a shift to a wild-type virus. This minority is rapidly reselected, perhaps from proviral DNA copies, once antiretroviral drugs to which the patients had already been exposed are reintroduced [15]. As confirmation of the critical role of new drugs introduced as part of salvage regimens, cohort studies have reported a sustained benefit from treatment during more recent periods of HAART [16]. It is possible that progressive addition of new drugs, together with increased experience and better understanding of clinical management and the effects of drug resistance, might produce this prolonged virological benefit and the continued fall in morbidity and mortality [16].
As its main result, the Reverse study confirmed the observations of the CPCRA 064 study: there were detrimental clinical effects of structured treatment interruption in patients with advanced disease who had experienced multiple drugs and had drug resistance [11,13]. However, both studies included patients with a median CD4 cell count < 200 x 106 cells/l, and a high rate (about 55%) of previous experience of AIDS-defining events. In the Retrogene study, which included patients with a median CD4 cell count > 300 x 106 cells/l, no adverse clinical events nor deaths occurred during follow-up, despite the absence of immunological benefit in the structured treatment interruption arm [10].
Certainly, the negative clinical results and the lack of virological and immunological benefit that comprehensively emerges from clinical studies of structured treatment interruption should advise against the use of this strategy in patients with advanced disease, multiple failed regimens, low CD4 cell count and previous experience of AIDS-related events. Yet, even though previous observations have shown that retained susceptibility to previous agents or classes may confer virological benefit in treatment-experienced patients with advanced disease [17], some evidence indicates that adding new antiretroviral drugs in this setting could result in a virological effect only if at least two or more active background antiretroviral agents were included [18]. Using a new drug, which was reported as active by genotyping or phenotyping, as a single agent would probably lead to accumulation of drug resistance and treatment failure. There is an increased risk of exhaustion of antiretroviral treatment options in individuals who have experienced three classes of antiretroviral drug [19] and a higher probability of clinical progression associated with multiclass drug resistance [20]. Consequently, structured treatment interruption could still represent a reasonable possibility for patients without effective therapeutic options; this would need to be tested by randomized studies involving only patients with multiple drug failure, relatively preserved CD4 cell counts and very limited therapeutic choices. In the absence of such studies, structured treatment interruption should not be used for routine clinical purpose, where strategies able to reduce the replicative capacity and virulence of the virus would still be preferable [21-22], or in situations of a failing regimen unless there are new therapeutic options to be utilized at resumption of therapy [4,23].
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