Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain
Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
Correspondence: Dr Juan A. Pineda, Infectious Diseases and Microbiology Unit, Hospital Universitario de Valme, Avda. Bellavista s/n, 41014 Seville, Spain. Tel: +34 955015684; fax: +34 955015795; e-mail: email@example.com
Nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens may be needed in patients with NRTI toxicity. Maraviroc (MVC) plus ritonavir-boosted darunavir (DRV-r) or atazanavir is associated with slightly lower response rates than triple therapy in drug-naïve patients. No information is available on these combinations in pretreated patients. The aim of this study was to assess the efficacy and safety of MVC plus DRV/r once-daily (qd) in HIV-infected pretreated patients.
A retrospective cohort study including patients starting MVC 150 mg plus DRV/r 800/100 mg qd, with CCR5 tropism and no resistance mutations for DRV/r, was performed. The primary efficacy endpoint was the achievement of plasma HIV RNA < 50 HIV-1 RNA copies/mL after 48 weeks. The frequency of serious adverse effects was investigated.
Sixty patients were recruited to the study, of whom 48 (80%) had HIV RNA < 50 copies/mL at baseline. Reasons for starting MVC plus DRV/r were: adverse effects in 38 individuals (63%), simplification in 15 (25%) and virological failure in seven (12%). The main analysis (intention to treat, noncompleter = failure) showed that 47 patients (78%) achieved HIV RNA < 50 copies/mL at 48 weeks (paired comparison with baseline, P = 1.0). On-treatment analysis showed that 42 (86%) of 49 patients presented HIV RNA < 50 copies/mL at 48 weeks (paired comparison with baseline, P = 1.0). Median (interquartile range) CD4 cell counts increased from 491 (301−729) to 561 (367−793) cells/μL at 48 weeks (P = 0.013). Only one patient discontinued therapy because of adverse effects.
Most individuals starting MVC plus DRV/r qd because of simplification or adverse effects maintained HIV suppression after 48 weeks of follow-up.
The paradigm of antiretroviral therapy is a combination of two nucleoside reverse transcriptase inhibitor (NRTIs) plus a third drug, most frequently a protease inhibitor (PI), nonnucleoside reverse transcriptase inhibitor (NNRTI) or integrase inhibitor . However, adverse effects such as lipodystrophy, mitochondrial toxicity, bone disorders, renal function impairment and increased cardiovascular risk have been reported as being associated with NRTI-based therapy [2-6]. Because of these long-term toxicities, NRTI-sparing regimens are now the subject of intense investigation.
One possible alternative to NRTI-based regimens is monotherapy with a ritonavir-boosted PI (PI/r). Concerns about PI/r monotherapy regimens include the higher frequency of blips and even failure to fulfil noninferiority criteria when compared in clinical trials with regimens consisting of two NRTIs plus PI/r [7, 8]. A second option for NRTI-sparing regimens is two-drug combinations. The first dual, two-class antiretroviral regimens evaluated were combinations of an NNRTI plus PI/r. However, combinations of efavirenz plus lopinavir/r showed significantly more laboratory side effects than three-drug NRTI-based regimens in the clinical trial AIDS Clinical Trials Group (ACTG) 5142 . The advent of new pharmacological families of antiretroviral drugs has enabled the evaluation of potentially safer and more effective regimens. Promising antiretroviral regimens include combinations of maraviroc (MVC) plus PI/r.
Current pharmacokinetic data support the use of MVC 150 mg once-daily (qd) in combination with darunavir/r (DRV/r) [10, 11]. Efficacy and safety data for MVC combined with PI/r are available from a pilot clinical trial that randomized antiretroviral drug-naïve patients to MVC 150 mg qd plus atazanavir/r (ATV/r) 300/100 qd or tenofovir/emtricitabine plus ATV/r qd . After 96 weeks of follow-up, the patients in the two-drug combination arm achieved lower rates of undetectable plasma HIV RNA; 68% patients in the MVC plus ATV/r arm vs. 82% individuals in the tenofovir/emtricitabine plus ATV/r group . In addition, a smaller exploratory, single-arm trial assigning drug-naïve patients to MVC 150 mg plus DRV/r 800/100 mg qd also showed a higher rate of virological failure, mainly among individuals with higher baseline HIV viral loads . Finally, a large clinical trial randomizing drug-naïve individuals to start MVC plus DRV/r or tenofovir/emtricitabine plus DRV/r was prematurely discontinued because of inferior efficacy in the MVC arm relative to the comparator arm . Thus, these dual drug regimens seem not to be appropriate for use in previously drug-naïve patients. However, the utility of MVC plus PI/r could be greater in the pretreated patient setting with controlled viral replication, where less drug potency may be required and safety is a major concern.
For these reasons, we assessed the frequency of plasma HIV RNA levels < 50 HIV-1 RNA copies/mL in antiretroviral drug-experienced HIV-infected patients after 48 weeks of receiving MVC 150 mg plus DRV/r 800/100 mg qd. In addition, we evaluated the frequency of serious adverse effects among these patients.
This was a post-licensing retrospective cohort study carried out in 11 centres in Andalusia, southern Spain. All HIV-infected patients who had been seen in the participating centres from January 2009 to June 2011 were included in the study if they fulfilled the following criteria: (1) age > 18 years; (2) previously treated with antiretroviral therapy; (3) starting a drug combination comprising MVC 150 mg qd plus DRV/r 800/100 mg qd; (4) CCR5 tropism demonstrated by a genotypic assay in plasma HIV RNA or proviral DNA before starting MVC; (5) no prior virological failure on PIs or, if any, evidence of no resistance to DRV/r during the episode of virological failure; (6) at least 1 week of continued antiretroviral therapy with MCV plus DRV/r.
Patients on antiretroviral therapy in the participating centres are followed with a common schedule of visits after starting a new antiretroviral regimen. During the first year of receiving a new drug combination, clinical visits are routinely planned at baseline, i.e. the date of starting the new drug combination, at weeks 4 and 12, and every 12 weeks thereafter up to 48 weeks. The data collected for the present study are routinely recorded as part of each clinical visit.
At baseline, the following data were obtained from the clinical records: date of birth, gender, clinical conditions, daily alcohol consumption, CD4 cell counts, HIV RNA load, risk factor for acquiring HIV, hepatitis C virus (HCV) RNA and hepatitis B virus surface antigen (HBsAg) test results, blood test results (including blood cell counts, liver function test results, and measurements of lipids and creatinine), antiretroviral drugs before starting MVC plus DRV/r, and reason to initiate MVC plus DRV/r. At each follow-up visit, the following data were collected from the clinical records: clinical conditions, side effects, self-reported adherence, CD4 cell counts, HIV RNA load and blood test results (including blood cell counts, liver function test results, and measurements of lipids and creatinine). If treatment was interrupted or changed, the reasons for doing so were recorded.
Genotypic tropism determination
For genotypic tropism determination, the V3 region of the envelope (env) gene of HIV-1 was amplified and sequences were interpreted using geno2pheno (http://www.genafro.org), with a 10% false-positive rate. Briefly, the V3 region was amplified from RNA in viraemic patients when the HIV viral load was > 200 copies/mL, or from proviral DNA if HIV viraemia was undetectable or < 200 copies/mL. For proviral DNA testing, peripheral blood mononuclear cells (PBMCs) were isolated from 10 mL of EDTA-K2 anti-coagulated whole blood using a Ficoll gradient. Following a nested polymerase chain reaction (PCR) protocol, the V3 region was subjected to bi-directional sequencing in the TrugeneTM platform (Bayer NAD, Barcelona, Spain) as previously described . Prior to interpretation in the geno2pheno system, V3 sequences were expanded into all possible combinations, and scored as X4 when just one of the generated sequences had a false-positive rate < 10%. Only sequences with fewer than eight ambiguities were considered as valid for tropism interpretation.
Assessment of severe adverse effects
At each scheduled visit, self-referred clinical adverse events were recorded. In addition, patients were asked about the most common side effects associated with antiretroviral drugs. Adverse clinical events were scored with the use of the adverse-event grading scale of the National Institutes of Health's Division of AIDS.
Laboratory parameters were also evaluated to assess adverse effects. Liver function tests were scored as follows. In patients with normal baseline levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), values of ALT or AST between 5 and 10 times the upper limit of the normal range were considered grade 3 transaminase elevations, while grade 4 elevations were defined as ALT or AST values > 10 times the upper limit of the normal range. When patients presented elevated baseline ALT or AST levels, an elevation between 3.5- and 5-fold was considered grade 3 elevation and a > 5-fold elevation grade 4.
The primary study endpoint was the frequency of plasma HIV RNA < 50 copies/mL 48 weeks after starting MVC plus DRV/r. Secondary endpoints were the development of severe adverse events and treatment discontinuations because of side effects. The primary analysis was carried out using an intent-to treat (ITT) approach. For this ITT analysis, patients lost to follow-up were considered as having treatment failure. In addition, a secondary sensitivity analysis adopting an ‘on-treatment’ strategy was performed including all patients who completed the follow-up while receiving the study drug combination. The frequency of adverse events was calculated during the first 48 weeks on MVC plus DRV/r.
Continuous variables are expressed as median (interquartile range (IQR)). Categorical variables are presented as number (percentage). The Wilcoxon signed-rank test was used for comparisons between two continuous variables, and the Friedman test for comparisons among more than two continuous variables. The McNemar test was used to compare two categorical variables. Statistical analyses were performed with the spss 19 software package (SPSS Inc., Chicago, IL).
The study was designed and conducted following the Helsinki declaration. The Ethics Committee of the Hospital Universitario de Valme approved the study.
Sixty patients were included in the cohort. The baseline characteristics of the patients are summarized in Table 1. Reasons to start MVC plus DRV/r were simplification of a previous drug combination in 15 patients (25%) and virological failure in seven (12%). Adverse effects were the reason for initiating MVC plus DRV/r in 38 individuals (63%). In 13 patients, the reason for changing therapy was lipoatrophy. Other side effects driving the initiation of MVC plus DRV/r were: dyslipidaemia in six patients, gastrointestinal symptoms in five, hypophosphataemia in five, Fanconi's syndrome in two, neuropsychiatric symptoms in two, hepatotoxicity in two, cardiovascular disease in two, and an increase in creatinine levels in one. Individual antiretroviral drugs used before starting MVC plus DRV/r are shown in Table 2. The disposition of patients is shown in Figure 1.
Table 1. Characteristics of the study population (n = 60)
Table 2. Individual antiretroviral drugs before switching to maraviroc plus ritonavir-boosted darunavir
Nucleoside reverse transcriptase inhibitors
Nonnucleoside reverse transcriptase inhibitors
Protease inhibitors boosted with ritonavir
Response to treatment
At baseline, 48 patients (80%) showed plasma HIV RNA < 50 copies/mL. The primary analysis (ITT) showed that 47 patients (78%) achieved plasma HIV RNA < 50 copies/mL at 48 weeks (paired comparison with baseline, P = 1.0). The proportion of patients with HIV viraemia < 50 copies/mL at each scheduled clinical visit thorough the first year on MVC plus DRV/r is shown in Figure 1. During follow-up, 11 patients did not complete 48 weeks of MVC plus DRV/r. Of these, three patients (5%) were lost to follow-up, two (3.3%) discontinued therapy, three (5%) showed virological failure, one (1.7%) changed to another regimen because of musculoskeletal pain attributed to MVC plus DRV/r, one (1.7%) switched to other antiretroviral drugs because of interactions with rifampin, and one patient (1.7%) died because of a non-AIDS-defining cancer. In the on-treatment analysis, 42 (86%) of 49 patients achieved plasma HIV RNA < 50 copies/mL at 48 weeks (paired comparison with baseline, P = 1.0). Median CD4 cell counts increased significantly during follow-up (Figure 2).
Of the seven patients starting MVC plus DRV/r because of virological failure, plasma HIV RNA < 50 copies/mL at 48 weeks was observed in two patients; two individuals showed low-level HIV viraemia at 48 weeks, i.e. 63 and 77 copies/mL, respectively; one patient failed to suppress HIV RNA; one patient achieved plasma HIV RNA < 50 copies/mL and then presented virological failure; and one patient discontinued MVC plus DRV/r because of drug−drug interactions.
Patients with virological failure during the 48-week study period showed the following levels of plasma HIV RNA at the date of loss of suppression: 1005, 2275 and 79 copies/mL. The first patient showed a change in genetic tropism to X4 strains, and no mutations associated with resistance either in the reverse transcriptase or in the protease gene. The second patient showed the 77I and 93L mutations in the protease region. It was not possible to obtain amplifications for resistance testing in the third patient. The viral strains remained R5-tropic in the second and third patients. HIV viral load was successfully suppressed in all of these patients after changing to triple therapy.
One individual discontinued MVC plus DRV/r because of musculoskeletal pain. Clinical adverse events during follow-up were not severe. Clinical adverse events recorded during follow-up were nausea (one patient; 1.6%), vomiting (one patient; 1.6%), diarrhoea (two patients; 3.3%), asthenia (one patient; 1.6%), tingling in the lower limbs (one patient; 1.6%) and musculoskeletal pain (one patient; 1.6%). Grade 3 or 4 laboratory abnormalities observed during the study period were AST elevations (one patient; 1.6%) and low-density lipoprotein (LDL) cholesterol levels > 190 mg/mL (three patients; 5%). In addition, severe elevations of ALT were observed in two patients (3.3%), at weeks 24 and 48 of therapy, respectively. Both ALT elevations were asymptomatic and subsided spontaneously.
Changes in selected blood test results are summarized in Table 3. Total cholesterol and high-density lipoprotein (HDL) cholesterol levels increased from baseline to 48 weeks of follow-up. The number of patients with total cholesterol > 200 mg/dL was 12 (25%) at baseline compared with 21 (43%) at 48 weeks (out of 49 patients with paired data; P = 0.022). LDL cholesterol levels and the total cholesterol:HDL cholesterol ratio did not increase significantly. Triglyceride levels > 150 mg/dL were observed in 20 subjects (41%) at the date of starting MVC plus DRV/r and 21 patients (43%) at 48 weeks of therapy (out of 49 individuals with paired data; P = 1.0). Creatinine clearance did not change significantly. Creatinine clearance < 80 mL/min/1.72 m2 at baseline was detected in 17 patients (31%) compared with 13 patients (27%) at 48 weeks (P = 1.0).
Table 3. Changes in blood tests between baseline and 48 weeks of treatment with maraviroc (MVC) plus ritonavir-boosted darunavir (DRV/r)
Liver function tests decreased significantly after 48 weeks of combination therapy with MVC plus DRV/r (Table 3). An analysis excluding the two patients who started MVC plus DRV/r because of liver toxicity related to the previous antiretroviral regimen yielded similar results. Median (IQR) ALT levels were 28 (19–48) IU/mL at baseline and 24 (16–29) IU/mL at 48 weeks (P = 0.021). Median (IQR) AST levels were 28 (18–48) at baseline and 17 (23–28) IU/mL at 48 weeks (P = 0.006). The AST to platelet ratio index (APRI) decreased significantly between baseline and the 48-week visit (Table 3). Similar results were obtained excluding the two patients with a change to MVC plus DRV/r because of hepatotoxicity, i.e. median (IQR) APRIs at baseline and at 48 weeks were 0.38 (0.23–0.83) and 0.31 (0.19–0.57), respectively (P = 0.024).
HIV-infected individuals previously exposed to antiretroviral drugs who started MVC 150 mg plus DRV/r 800/100 mg qd because of simplification or adverse effects maintained HIV suppression in most instances in a real-life setting. This combination was well tolerated, with no unexpected side effects.
The results of this observational study may contrast with those of recently reported clinical trials recruiting antiretroviral drug-naïve patients [12, 13]. A pilot trial randomizing patients to MVC plus ATV/r or tenofovir/emtricitabine plus ATV/r showed lower response rates for the dual therapy arm . In a pilot study on 24 patients combining MVC 150 mg with DRV/r 800/100 mg as a once-daily first-line regimen, three of four virological failures after 48 weeks occurred in individuals with a pretreatment viral load > 100 000 copies/mL . One possible explanation for the lower than expected response rates is that the double drug combination of MVC plus a PI/r may lack the potency to achieve the HIV suppression rates observed with standard triple therapy. However, the viral decay with MVC plus DRV was comparable to that for the efavirenz-containing three-drug regimen in a subanalysis of the MIDAS trial . Thus, it is conceivable that the virological response to MVC plus DRV/r is similar to that of combinations including efavirenz. In the present study, there was no signal of low potency related to MVC plus DRV/r. Pretreated individuals who were selected to receive that combination, because of CCR5 tropism and lack of resistance mutations for DRV/r, did well and no significant changes in the proportion of patients with HIV suppression were observed. However, a longer follow-up of patients switching to MVC plus DRV/r is warranted to establish the long-term efficacy of this strategy.
Seven individuals started MVC plus DRV/r because of virological failure on a previous antiretroviral regimen. Two of these patients showed undetectable plasma HIV RNA and another two individuals low-level viraemia at week 48. In an additional patient, MVC plus DRV/r was discontinued because of drug−drug interactions. Thus, it is difficult to draw conclusions based on these data, but the dual combination of MVC plus DRV/r does not seem advisable as rescue therapy for failing regimens.
Liver function tests and APRI decreased during the first 48 weeks on MVC plus DRV/r. This effect was not attributable to switches because of liver toxicity, as a subanalysis excluding two patients who started MVC plus DRV/r because of previous liver toxicity yielded the same results. Alternatively, the initiation of an NRTI-sparing regimen could reduce the grade of pre-existing hepatic steatosis or steatohepatitis. In particular, the use of either MVC or DRV/r has shown a univariate association with a lower likelihood of hepatic steatosis in a cross-sectional survey . Thus, a regimen including both might provide some additional benefit in terms of preventing fatty liver disease in these patients. In addition, serum mediators of liver fibrogenesis and fibrosis do not change significantly in HIV/HCV-coinfected patients in the short term after starting MVC, while their natural history is to increase over time in HCV infection . In the study population, composed mainly of patients without HCV coinfection, the effect of MVC on mediators of liver fibrogenesis might have contributed less to the observed changes in liver function tests.
No unexpected side effects were recorded during the first 48 weeks on MVC plus DRV/r. Only one patient interrupted the combination because of symptoms that emerged after starting MVC plus DRV/r. The lipid profile did not worsen in study patients after starting MVC plus DRV/r. The total:HDL cholesterol and HDL:LDL cholesterol ratios did not change significantly. Regarding renal function, no significant changes were observed in creatinine clearance and phosphate blood levels. However, very few patients showed altered creatinine clearance at baseline. Among drug-naïve patients, creatinine clearance dropped slightly after 96 weeks in those starting MVC plus ATV/r . In the present study, carried out in pretreated patients receiving MVC plus DRV/r, renal function was preserved over 48 weeks.
This study has several limitations. First, this was a retrospective cohort study of patients previously treated with antiretroviral therapy who started MVC plus DRV/r. Thus, the cohort is comprised of individuals starting this dual therapy for reasons of toxicity and simplification and, to a lesser extent, patients initiating MVC plus DRV/r because of virological failure. This heterogeneous group of patients, however, allows the main conclusion of the present study to be drawn. In the setting of experienced patients, with evidence of CCR5 viral tropism, low HIV viral load and absence of relevant resistance mutations, MVC 150 mg plus DRV/r 800/100 mg qd is effective to maintain HIV suppression without increasing side effects. Secondly, some data, particularly regarding mild side effects, might be lost or underreported because of the retrospective design. However, patients are followed at the participating centres with fixed scheduled clinical visits and a similar procedure for data recording. The data gathered for the present study are routinely included in the follow-up protocols of the participating centres and entered in the clinical records. Thirdly, the sample size of the present study was relatively small and thus might lack power to detect differences in terms of the proportion of patients with HIV RNA load < 50 copies/mL at the end of the follow-up period. However, no trend towards a reduction in the proportion of patients with controlled HIV infection was observed. This finding leads us to believe that this limitation did not affect our results.
In conclusion, MVC 150 mg plus DRV/r 800/100 mg qd seems to be a regimen that can be effectively used in antiretroviral drug-pretreated individuals with controlled HIV infection. The tolerability of this dual combination can prevent the accumulation of adverse events associated with NRTI-containing drug regimens. Randomized clinical trials are needed to establish the efficacy and safety of MVC plus DRV/r among pretreated patients. In an ageing HIV-infected population, with increasing comorbidities, MVC plus DRV/r could be a safer option than standard triple therapy.
JAP has received a research extension grant from the Programa de Intensificación de la Actividad de Investigación del Servicio Nacional de Salud español (I3SNS). JMS has received human resources research support from Servicio Andaluz de Salud de la Junta de Andalucía (Reference B-0037). The authors thank the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Red de SIDA of Spain for their support (ISCIII-RETIC RD06/006 and RD12/0017) and the Consejería de Salud, Junta de Andalucía (Reference SAS-111212).
Conflicts of interest: JM has been an investigator in clinical trials supported by Roche, Bristol-Myers Squibb and Abbott Pharmaceuticals. He has received lectures fees from Roche, Gilead, Boehringer Ingelheim and Bristol-Myers Squibb, and consulting fees from Boehringer Ingelheim, Bristol Myers-Squibb and Merck Sharp & Dome. DM reports having received consulting fees from Abbott, Gilead, Bristol-Myers Squibb, Jansen Cilag and ViiV y Gilead. JAP reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott, Gilead, Merck Sharp & Dome, Jansen Cilag and Boehringer Ingelheim. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott and Boehringer Ingelheim and has received lecture fees from GlaxoSmithKline, Roche, Abbott, Bristol-Myers Squibb, Boehringer Ingelheim and Schering-Plough. The remaining authors report no conflicts of interest.