Predictors of long-term HIV RNA suppression on darunavir/ritonavir monotherapy in the MONET trial

Abstract

European HIV treatment guidelines include the option for patients to switch to protease inhibitor (PI) monotherapy (either darunavir/ritonavir or lopinavir/ritonavir) if their HIV RNA levels are suppressed and they have no history of virological failure.¹ However, two systematic reviews have shown a higher rate of virological failure in patients who switched to PI monotherapy compared to those who received standard triple combination therapy.^2,3 In previous studies of PI monotherapy as a switch option, patients with higher nadir CD4 counts, baseline HIV RNA < 1 copy/mL, and high adherence to treatment have been most likely to achieve sustained HIV RNA suppression of <50 copies/mL.^4–6 A meta-analysis of 10 clinical trials has shown a significantly higher risk of antiretroviral treatment failure in patients co-infected with hepatitis C virus (HCV).⁷ We re-analysed the results from the MONET trial⁸ to assess predictors of long-term HIV RNA suppression.

The design and outcomes of the MONET trial have been published previously.⁸ Briefly, the trial recruited 256 patients with HIV RNA < 50 copies/mL for at least six months before screening, nadir CD4 counts above 100 cells/µL, and no history of virological failure. The patients were randomised to receive 144 weeks of treatment with darunavir/ritonavir 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside reverse transcriptase inhibitors (triple therapy arm) (n = 129). HIV RNA was assessed using the Roche Amplicor ultrasensitive assay (Roche, Branchburg, New Jersey, USA) at a centralised laboratory. Hepatitis C co-infection was assessed using antibody testing, but there was no systematic evaluation of HCV viral load. At the baseline visit, HIV RNA results were classified as <5 (no detection), 5–49 (virus detected under quantification limit), or ≥50 copies/mL.

In the primary efficacy analysis, treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL by week 144, or discontinuation of study drugs. Patients could intensify or switch their treatment after sustained elevations in HIV RNA. We used multiple logistic regression to correlate treatment failure with age, sex, body weight, nadir CD4 count, baseline CD4 count, baseline HIV RNA, hepatitis C co-infection, and prior use of PI treatment. We conducted this analysis first for the Intent to Treat (ITT) switch equals failure endpoint, where any elevation in HIV RNA was classified as failure, regardless of subsequent re-suppression. Then we repeated the analysis for the ITT switch-included endpoint, which classified patients as successes if their HIV RNA level was <50 copies/mL at week 144, regardless of changes in treatment made before this time.

At the baseline visit, the number of patients with hepatitis C (HCV) antibodies was 24/127 (19%) in the monotherapy arm and 15/129 (12%) in the triple therapy arm; the number of patients with HIV RNA levels above 5 copies/mL at baseline was 24/127 (20%) in the monotherapy arm and 29/129 (21%) in the triple therapy arm. By week 144, using the primary ITT switch equals failure analysis, the number of randomised patients with HIV RNA < 50 copies/mL was 88/127 (69%) in the darunavir/ritonavir monotherapy arm versus 97/129 (75%) in the triple therapy arm. In the switch-included analysis (including re-suppression of HIV RNA as success), the number of patients with HIV RNA < 50 copies/mL was 106/127 (83%) in the darunavir/ritonavir monotherapy arm and 106/129 (82%) in the triple therapy arm.

In the multivariate analysis for the primary ITT switch equals failure endpoint, positive HCV serology correlated with treatment failure (odds ratio [OR] = 2.44, 95% CI [confidence interval], 1.20–5.00). In the switch-included analysis, only HIV RNA > 5 copies/mL was predictive of treatment failure (OR = 2.78, 95% CI, 1.28–6.01). Nadir or baseline CD4 count, sex, body weight, and prior PI use were not predictive of treatment failure in any analysis.

Table 1 shows a sub-group analysis of HIV RNA suppression at week 144, by baseline HIV RNA levels and hepatitis C serology. In the switch equals failure analysis, the percentage of patients with HIV RNA < 50 copies/mL at week 144 was similar in the two treatment arms for the subset of patients with no HCV co-infection (based on serology) and HIV RNA levels below 5 copies/mL at baseline. However, in this exploratory analysis, there was lower efficacy in the monotherapy arm for patients who had HCV co-infection, baseline HIV RNA > 5 copies/mL, or both risk factors. However, in the switch-included analysis, where re-suppression of HIV RNA at week 144 was classified as success, there were similar rates of efficacy in the two treatment arms across three of the four sub-groups.

Table 1.

HIV RNA <50 copies/mL at week 144 by HCV antibody status and HIV RNA <5 copies/mL at baseline.

Baseline		HIV RNA <50 copies/mL at week 144
HCV Ab	HIV RNA	DRV/r arm (n = 127)	DRV/r + 2NRTI arm (n = 129)
ITT switch equals failure analysis
HCV−	<5 copies/mL	66/84 = 79%	67/90 = 74%
HCV−	≥5 copies/mL	12/19 = 63%	19/24 = 79%
HCV+	<5 copies/mL	9/19 = 47%	9/10 = 90%
HCV+	≥5 copies/mL	1/5 = 20%	2/5 = 40%
ITT switch-included analysis
HCV−	<5 copies/mL	73/84 = 87%	75/90 = 83%
HCV−	≥5 copies/mL	13/19 = 68%	18/24 = 75%
HCV+	<5 copies/mL	17/19 = 89%	9/10 = 90%
HCV+	≥5 copies/mL	3/5 = 60%	4/5 = 80%

This analysis has several limitations. Firstly, this is a post-hoc exploratory analysis of the MONET trial, which was not statistically powered to evaluate efficacy in these sub-groups. Secondly, the sample sizes are small for some of the sub-groups, particularly the patients who were both co-infected with hepatitis C and had HIV RNA levels above 5 copies/mL. The size of the sub-groups may have limited the statistical power to show significant associations between baseline factors and response. Thirdly, the Roche Amplicor Ultrasensitive assay was used to measure HIV RNA levels – this assay normally has a lower limit of quantification of 50 copies/mL, but traces of HIV RNA can be detected down to levels of 5 copies/mL. This analysis should be repeated using more modern assays in routine use, such as the Roche Taqman or Abbott REALTIME assays. In addition, co-infection with hepatitis C was defined only from antibody testing at baseline. There was no systematic collection of HCV viral load data to confirm chronic HCV infection. There were three patients who became acutely infected with HCV during the trial (all in the DRV/r monotherapy arm). These patients were analysed as HCV negative at baseline.

Patients with HCV co-infection in the MONET trial were less adherent to trial medication by self-reported questionnaire. In addition, the HCV co-infected patients were predominantly former or current injection drug users, with lower baseline CD4 cell counts than the patients infected with HIV alone.⁸ It is unclear whether HCV co-infection is a marker for poor adherence, or whether HCV viraemia may increase the risk of elevations in HIV RNA.

In summary, patients without HCV co-infection (based on serology), and with baseline HIV RNA < 5 copies/mL by the Roche Amplicor assay (i.e. no virus detected) showed the highest rates of sustained HIV RNA suppression < 50 copies/mL on darunavir/ritonavir monotherapy. However, patients who showed elevations in HIV RNA above 50 copies/mL could be successfully re-suppressed after intensification with nucleoside analogues. When the outcomes of treatment intensification were included in the analysis, the probability of HIV RNA suppression at week 144 was similar between the monotherapy and triple therapy arms in the main sub-groups analysed. These analyses may help to identify patients most likely to show HIV RNA rebound during PI monotherapy, who could then be re-suppressed after treatment intensification. The sample sizes are small for some of the sub-groups analysed, and so these analyses need to be confirmed in other large randomised trials of PI monotherapy.

Footnotes

Funding

The MONET trial was funded and sponsored by Janssen Europe.

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