Long‐term (96‐week) follow‐up of antiretroviral‐naïve HIV‐infected patients treated with first‐line lopinavir/ritonavir monotherapy in the MONARK trial*

Background

The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral‐naïve patients.

Methods

A total of 136 antiretroviral‐naïve patients, with a CD4 cell count above 100 cells/μL and a plasma HIV RNA below 100 000 HIV‐1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n=83) or lopinavir/ritonavir+zidovudine/lamivudine (n=53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent‐to‐treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n=83), and then focused on patients who had an HIV RNA <50 copies/mL at week 48 (n=56).

Results

At week 96, 39 of 83 patients (47%) had HIV RNA <50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA >400 copies/mL. Focusing on the 56 patients with an HIV RNA <50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA <50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI‐associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96.

Conclusion

By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA <50 copies/mL at week 96. The occurrence in some patients of low‐level viraemia (50–500 copies/mL) may increase the risk of drug resistance. First‐line lopinavir/ritonavir monotherapy cannot be systematically recommended.     

Persistent low-level viraemia and virological failure in HIV-1-infected patients treated with highly active antiretroviral therapy

OBJECTIVE: To assess the prognostic significance of persistent low-level viraemia (PLV, defined as persistent plasma viral loads of 51-1000 HIV-1 RNA copies/mL for at least 3 months) in patients who had achieved viral suppression on antiretroviral therapy (ART). METHODS: A retrospective cohort of HIV-infected patients who received ART, were followed-up for > or =12 months, made regular visits to the clinic during which blood tests were performed for an ultrasensitive HIV RNA assay every 3 months, and achieved viral loads <50 copies/mL were evaluated. Virological failure was defined as two consecutive viral load measurements >1000 copies/mL. RESULTS: Of 362 patients, 78 (27.5%) experienced PLV. The demographics of patients with and without PLV were similar. PLV occurred at a mean (+/-standard deviation) of 22.6+/-16.9 months after ART initiation and lasted for 6.4+/-3.4 months. During a median follow-up of 29.5 months, patients with PLV had a higher rate of virological failure (39.7% vs 9.2%; P < 0.001). The median time to failure was 68.4 months [95% confidence interval (CI) 37.0-99.7] for patients with PLV and >72 months for patients without PLV (log rank test, P < 0.001). By Cox regression, patients with PLV had a greater risk of virological failure [hazard ratio (HR) 3.8; 95% CI 2.2-6.4; P < 0.001]. Among patients with PLV, a PLV of >400 copies/mL (HR 3.3; 95% CI 1.5-7.1; P = 0.003) and a history of ART (HR 2.4; 95% CI 1.0-5.7; P = 0.042) predicted virological failure. CONCLUSIONS: PLV is associated with virological failure. Patients with a PLV >400 copies/mL and a history of ART experience are more likely to experience virological failure. Patients with PLV should be considered for treatment optimization and interventional studies.     

Mid‐dosing interval concentration of atazanavir and virological outcome in patients treated for HIV‐1 infection

Objectives

We investigated the clinical significance of monitoring the mid‐dosing interval atazanavir (ATV) concentration (measured 12 ± 2 h after intake; C_{12 h}) in patients taking this drug once daily in the evening.

Methods

We retrospectively selected HIV‐infected patients harbouring ATV‐susceptible virus who underwent therapeutic drug monitoring (TDM) of ATV C_{12 h} during routine out‐patient visits, and we correlated C_{12 h} to the 24‐week virological response and toxicity.

Results

A total of 115 plasma samples from 86 patients (76.7% with baseline HIV RNA<50 HIV‐1 RNA copies/mL) were analysed. ATV plasma concentrations showed high inter‐individual variability. ATV plasma levels were higher in samples obtained from patients taking boosted regimens (P<0.001) and not concomitantly receiving acid‐reducing agents (P=0.007). In a multivariate model, ritonavir boosting, use of acid‐reducing agents and liver cirrhosis showed an independent association with ATV level. Virological response at 24 weeks was observed for 94 of the 115 samples (81.7%). We identified a concentration cut‐off of 0.23 mg/L which predicted virological response at 24 weeks: samples with a C_{12 h}≤0.23 mg/L showed virological failure in 41.2% of cases, whereas samples with a C_{12 h}>0.23 mg/L showed virological failure in 14.3% of cases (P=0.021). In multivariate analysis, C_{12 h}>0.23 mg/L was an independent predictor of virological response [odds ratio (OR) 4.23, P=0.031]. ATV levels correlated with concomitant unconjugated bilirubin levels (r=0.223, P=0.037), but a concentration cut‐off predictive of moderate/severe hyperbilirubinaemia could not be identified.

Conclusions

We identified a C_{12 h} efficacy threshold that predicted virological response; this could be useful for morning TDM in selected subjects receiving ATV in the evening. Results must be interpreted with caution given the retrospective design of the study.

     

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study

Objective

The aim of the study was to describe trends in CD4 cell counts in HIV‐infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends.

Methods

Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviral‐naïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post‐cART virological failure. Effects of post‐cART virological failure (>1000 HIV‐1 RNA copies/mL) on subsequent CD4 cell counts were evaluated.

Findings

A total of 7069 participants were included in the analysis (median follow‐up in all baseline CD4 cell count groups was ≥35 months). Among participants without virological failure ≥6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load.

Conclusions

Post‐cART CD4 cell counts are strongly related to pre‐cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.     

Lopinavir/ritonavir monotherapy as maintenance treatment in HIV-infected individuals with virological suppression: results from a pilot study in Brazil

OBJECTIVE: The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression. DESIGN: This was a single-armed single-centre pilot trial. METHODS: Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated. RESULTS: All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4-23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed. CONCLUSIONS: LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up.