Abstract
We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2–34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.
Introduction
Three placebo-controlled clinical studies have proven that raltegravir added to optimized background treatment (OBT) in patients with virological failure may be effective in achieving an undetectable viral load and a significant CD4 increase in the majority of patients, even in the presence of limited therapeutic options and of triple-class drug-resistant HIV strains.
In the BENCHMRK 1 and 2 trials, suppression of plasma HIV-RNA below 50 copies/mL at 48 weeks was achieved in 62.1% of the raltegravir plus OBT recipients, compared with 32.9% of the placebo plus OBT recipients. 1 Week 96 results of the same trials confirmed the better viral suppression with raltegravir on a longer follow-up: 57% of patients (compared with 26% of placebo recipients) achieved an HIV plasma viral load below 50 copies per mL, with significantly better mean changes in HIV-RNA and CD4 cell counts in the raltegravir group. 2 Data from the 005 Protocol also demonstrated a better virological response with raltegravir plus OBT compared with OBT alone, both at 48 and 96 weeks. Response rates (defined by HIV-RNA values <50 copies/mL) in patients receiving raltegravir were 55% and 48% at 48 and 96 weeks, respectively. 3 In these studies, raltegravir was well tolerated, and only a very few patients discontinued the drug because of adverse events.
The above results were collected within placebo-controlled clinical trials. However, it is not clear whether similar response rates can be expected in a context of common clinical practice, where less selective clinical and laboratory criteria for admission to treatment may be responsible for a lower effectiveness of the regimens, and the use of new drugs, such as darunavir, etravirine and maraviroc, may further improve the rate and/or the sustainability of response.4–6 In order to define the actual rates and possible baseline determinants of virological response to raltegravir-based regimens in a setting of current clinical practice, we evaluated 48-week data from a national observational study of triple-class experienced patients.
Methods
We used data from the ISS-NIA (Istituto Superiore di Sanità – New Inhibitors Against HIV Study), an observational cohort study designed to evaluate in a setting of common clinical practice the effects of starting anti-HIV regimens based on integrase inhibitors and CCR5 inhibitors. Only triple-class (nucleoside reverse transcriptase inhibitor [NRTI], non-nucleoside reverse transcriptase inhibitors [NNRTI] and protease inhibitors [PIs]) drug-experienced patients with treatment failure, resistance or intolerance are eligible for the study. The study received ethics approval, and all patients gave written informed consent. The study started in 2008 and enrolment was closed in late 2010. Patients will be followed for at least three years.
All patients with detectable (>50 copies/mL) plasma HIV-1 RNA at baseline who received raltegravir and had a completed study follow-up status at 12 months were eligible for the analysis. The results reported refer to data available up to November 2010. The following study time points were used: baseline, month 3 (2 to 4), month 6 (5–7), month 9 (8–10) and month 12 (11–13).
A cumulative genotypic susceptibility score (GSS) was calculated for each regimen at the start of raltegravir. The GSS represented the sum of the individual susceptibility scores of each drug, raltegravir excluded. Susceptibility was defined using the Stanford HIV Resistance Database interpretation of the virus genotype (http://hivdb.stanford.edu/), with susceptibility scores for each drug defined as follows: 1.0 = susceptible or potential low-level resistance; 0.5 = low-level or intermediate resistance; and 0 = high-level resistance.
The main outcome measure was represented by virological treatment failure within 12 months, defined by any one of the following: (1) lack of HIV-1 RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) one detectable HIV-1 RNA viral load after obtaining undetectable levels; (3) leaving the study before 12 months of follow-up. Potential predictive factors were examined comparing groups of patients with and without virological treatment failure. The main analysis was based on an intent-to-treat (ITT), missing = failure approach that included all patients and considered patients with missing data as failures. Rate of virological failure was also reported according to an as-treated approach that excluded study non-completers.
Demographic, clinical and virological characteristics were compared by the Student's t-test for quantitative variables and by Pearson's chi-squared test or Fisher's exact test for qualitative variables. Baseline health-related quality of life (HRQoL) was measured using the Istituto Superiore di Sanità Quality of Life (ISSQoL) self-administered instrument 7 in a subgroup of patients who agreed to complete the questionnaire. All analyses were performed using the SPSS software, version 17.0 (SPSS Inc, Chicago, IL, USA).
Results
Overall, 101 patients were eligible for the analysis. They were more commonly men (68.3%), of Caucasian ethnicity (94.1%), and clinically symptomatic with respect to history of HIV disease (CDC Group B or C: 66.3%). Median values for age, CD4 T-cell counts and HIV-1 RNA at baseline were 46 years, 271 cells per mm3 and 4.2 log10 copies/mL, respectively. Co-infection with hepatitis viruses was relatively common (HCV 33.7%; HBV 9.9%). At the start of raltegravir treatment, patients had a long previous history of antiretroviral therapy (ART) (median: 12.1 years), and a very high frequency (74.3%) of triple-class resistance (NRTI, NNRTI, PI). Concomitant ART was highly heterogeneous; the raltegravir-based regimens included most frequently PI (80.2%) and NRTI (74.3%), followed by NNRTI (22.8%), CCR5 inhibitors (maraviroc: 20.8%) and fusion inhibitors (enfuvirtide: 16.8%). The individual drugs most commonly used, excluding low-dose ritonavir as a booster for other PI (87.7%), were darunavir (61.4%), tenofovir (44.6%), emtricitabine (39.6%), lamivudine (26.8%) and etravirine (21.8%). Drug sensitivity, based on the last genotyping test (available in 86 patients, in about 50% of cases within 24 weeks from switching to raltegravir) showed that 71 patients (82.5%) had at least two active drug classes (including integrase inhibitors) in the regimen.
Six patients left the cohort in the first 12 months. Two of them died from neoplastic diseases (non-Hodgkin's lymphoma and liver carcinoma), one left the study following virological treatment failure, two were transferred and one was lost to follow-up.
Overall, 26 patients (25.7%; 95% CI 17.2–34.2) had virological failure by 12 months in the ITT analysis. Most of them (15,14.8%) had a detectable viral load after obtaining undetectable levels; Five (4.9%) never had HIV-RNA levels below 50 copies/mL during follow-up, and six (5.9%) were study non-completers. Two of the non-completers had virological failure following successful viral suppression. When the four non-completers who did not meet the virological treatment failure criteria were excluded from the analysis, the rate of virological failure was 22/97 (22.7%; 95% CI 14.3–31.0) in the as-treated analysis. When using an HIV RNA polymerase chain reaction (PCR) cut-off of >200 copies/mL to define virological failure, as suggested by the most recent DHHS guidelines, 8 the rate of virological failure was 16.8% in the ITT and 13.4% in the as-treated analysis.
Rates of virological response during follow-up (HIV-RNA <50 copies/mL) were 77.7% (73/94) at three months, 79.1% (72/91) at six months and 82.7% (62/75) at nine months.
The individual characteristics of the 26 patients with virological failure are shown in Table 1. The comparisons between patients with and without virological failure for demographic, clinical and virological baseline characteristics (including genotypic sensitivity and number of active drugs) showed no clinically significant differences between the two groups (Table 2). A smaller group of patients with and without virological failure (n = 15 and 48, respectively) were also evaluated for HRQoL, and no statistically significant differences were observed in HRQoL dimensions between the two groups (data not shown).
Individual baseline characteristics of failing patients
HBV = hepatitis B; HCV = hepatitis C; IVDU = intravenous drug user; MSM = men who have sex with men; CDC = Centers for Disease Control and Prevention; CI = CCR5 inhibitors; FI = fusion inhibitors; II = integrase inhibitors; NRTI = nucleoside/nucleotide reverse transcriptase inhibitors; NNRTI = non-nucleoside reverse transcriptase inhibitors; PI = protease inhibitors; TDF = tenofovir; FTC = emtricitabine; ATV = atazanavir; 3TC = lamivudine; SQV/r = saquinavir/ritonavir; MVC = maraviroc; DRV/r = darunavir/ritonavir; ABC = abacavir; ENF = enfuvirtide; ETV = etravirine; ZDV = zidovudine; d4T = stavudine; EFV = efavirenz *nc = non-completer; f = failing; nr = non-responder; nc/f = non-completer with failure
General baseline characteristics of patients with and without subsequent virological failure
ARV = antiretroviral treatment; CI = CCR5 inhibitors; FI = fusion inhibitors; II = integrase inhibitors; NRTI = nucleoside/nucleotide reverse transcriptase inhibitors; NNRTI = non-nucleoside reverse transcriptase inhibitors; PI = protease inhibitors; SD = standard deviation; CDC = Centers for Disease Control and Prevention
Raltegravir/Integrase inhibitors excluded
Discussion
The present study showed in a setting of clinical practice a favourable virological outcome at 48 weeks among heavily pre-treated patients switching to raltegravir plus OBT, despite a long treatment history and a high percentage of triple-class resistance.9,10 Using a conservative ‘missing equal failure’ approach, treatment success, defined as a viral load below 50 copies/mL, was observed in 74.3% of the subjects. This proportion is higher compared with the overall rate of success at 48 weeks in the patients who received raltegravir within the BENCHMRK-1 and BENCHMRK-2 trials (62%). 1 The patients enrolled in the present cohort had slightly lower median baseline HIV-RNA levels (4.2 log versus 4.8), and a better baseline immunological status compared with the patients in the BENCHMRK studies (median CD4: 271 versus 119 mm” 3 , respectively).
It is important to consider that enrolment of BENCHMRK-1 and BENCHMRK-2 studies was closed in 2007, when important new drugs commonly used as OBT in our study, such as etravirine and maraviroc, were not yet available. It is therefore likely that the high rate of response observed in our cohort may reflect the current availability of a wider therapeutic armamentarium against HIV and relatively frequent use of these two drugs (maraviroc 20.8%, etravirine 21.8%), together with a more diffuse use of darunavir/ritonavir (61.4% in our study, 40% in BENCHMRK studies). In fact, our success rate is similar to the success rates described by Cooper et al. 11 in the subgroup of patients from the BENCHMRK trials that were using darunavir/r (69%), enfuvirtide (80%) or both (89%), respectively, in addition to raltegravir.
It is also important to note that the constraints induced by the limited follow-up, that precluded a long-term evaluation of some patients with low-level viraemia, prompted us to adopt a conservative approach, that included in the definition of treatment failure also low level HIV-RNA values that could represent either transient blips usually ignored in therapeutic decisions or the initial phase of a significant HIV-RNA rise. When using a HIV RNA PCR cut-off of >200 copies/mL, treatment success rates were even above 80%.
In our study, we were not able to find a significant relationship between use of any individual drug and treatment success, and to find any baseline predictor of failure in this group, when evaluating a number of potential indexes including validated prognostic measures such as baseline CD4 count, HIV-1 RNA levels, available genotypic resistance test results, and HRQoL measures.
The absence of evident predictors of virological failure in our study may be explained in different ways. First, we cannot exclude that we failed to detect any significant effect of some baseline variables because of a relatively small sample size or relatively limited follow-up. A recent genotypic test and a complete treatment history were also not available for all the patients included. Finally, we cannot exclude the presence at baseline of minority variants not detected by standard resistance assays. 12
Despite such limitations, the absence of baseline predictors of failure suggests that particular attention should be paid to other events occurring during follow up, which may have a significant impact on the development of treatment failure. These may be represented by reduced levels of adherence, decreased plasma drug levels caused by individual variability or drug interactions and accumulation of new resistance mutations. A careful monitoring in such patients may be particularly relevant because of the very limited residual therapeutic options left in the case of failure or resistance.
Footnotes
Acknowledgements
The ISS-NIA study group: G Angarano, N Ladisa, A Volpe, Clinic of Infectious Diseases, University of Bari; V Vullo, G D'Ettorre, G Ceccarelli, Department of Infectious Diseases, La Sapienza University, Rome; M Andreoni, L Sarmati, D Delle Rose, Infectious Diseases Unit, Tor Vergata University, Rome; V Tozzi, P Narciso, N Petrosillo, R Bellagamba, R Libertone, S Cicalini, C Tommasi, INMI ‘Lazzaro Spallanzani’, Rome; L Sighinolfi, D Segala, Infectious Diseases Unit, Arcispedale S Anna, Ferrara; O Armignacco, R Preziosi, ASL Viterbo, Belcolle Hospital, Viterbo; C Ferrari, A Degli Antoni, A Cavalli, Ospedale Maggiore, Parma; G Parruti, F Sozio, L Cosentino, Infectious Diseases Unit, Presidio Ospedaliero Santo Spirito, Pescara; A Vivarelli, Infectious Diseases Unit, Ospedale Civile, Pistoia; PE Manconi, F Ortu, University Policlinic, Cagliari; P Viale, G Verucchi, S Tedeschi, R Manfredi, Infectious Diseases Section, University and Policlinico S Orsola, Bologna; M S Mura, M Mannazzu, G Cattari, Clinic of Infectious Diseases, University of Sassari; M Tavio, R Del Gobbo, A Mataloni Paggi, Infectious Diseases Unit, Ospedali Riuniti, Torrette, Ancona; A Giacometti, O Cirioni, E Marchionni, E Gabrielli, L Brescini, S Sebastianelli, Clinic of Infectious Diseases, Ospedali Riuniti, University of Ancona; F Baldelli, D Francisci, A Mercuri, S Bastianelli, Ospedale S Maria della Misericordia and University of Perugia; G Guaraldi, G Nardini, Department of Internal Medicine, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Modena; R Bucciardini, M Floridia, LE Weimer, V Fragola, M Massella, S Baroncelli, CM Galluzzo, MF Pirillo, MG Mancini, R Amici, A Cara, R Bona, P Leone, P Filati, M Franco, S Donnini, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome.
We thank Stefania Donnini and Alessandra Mattei for secretarial help. The study was funded by a grant from the National Program on Research on AIDS 2009–2010. No funding was received for this work from any of the following organizations: National Institutes of Health (NIH); Wellcome Trust and the Howard Hughes Medical Institute (HHMI).