CROI: Once daily Kaletra may be less effective when viral load above 100,000 copies/ml

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Dosing Kaletra (lopinavir/ritonavir) once daily may be less effective than twice daily dosing in patients with high viral load (above 100,000 copies/ml), according to a large randomised study presented on Wednesday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.

The study also found that when considering viral suppression, a slight advantage to directly-observed therapy apparent at week 24 was lost after the DOT group switched to self-administered therapy, suggesting that early DOT does not have a long-term impact on the success of treatment; its effect appears confined to the period that DOT is actually taking place.

The ACTG A5073 study, which lasted for 48 weeks, was open-label and included 402 antiretroviral treatment-naïve patients who were recruited from treatment centres in the US and Puerto Rico. The study was sponsored by the US government-funded AIDS Clinical Trials Group.

Glossary

directly observed therapy (DOT)

When a health care professional watches as a person takes each dose of a medication, to verify that all doses are taken as prescribed.

open-label

A clinical trial where both the researcher and participants know who is taking the experimental treatment. 

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

opportunistic infection (OI)

An infection that occurs more frequently or is more severe in people with weakened immune systems, such as people with low CD4 counts, than in people with healthy immune systems. Opportunistic infections common in people with advanced HIV disease include Pneumocystis jiroveci pneumonia; Kaposi sarcoma; cryptosporidiosis; histoplasmosis; other parasitic, viral, and fungal infections; and some types of cancer. 

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

All the patients received background therapy consisting of FTC with tenofovir or d4T extended release (approximately two-thirds received d4T). They were also provided with Kaletra soft gel, but the dose of the drug they were provided with, and the way in which they took it (self-administered or directly-observed therapy), differed according to which of three study arms individuals were randomised to.

The first arm received a soft gel Kaletra dose of 400mg lopinavir/100mg ritonavir twice daily. The second arm was provided with a once-daily dose of Kaletra consisting of 800mg of lopinavir/200mg ritonavir. Patients in both of these arms took their medication without observation from healthcare workers.

However, the patients in the third arm were provided with a once-daily Kaletra dose (800mg lopinavir/200mg ritonavir) administered via directly observed therapy on week days for the first 24 weeks of the study and, self-administered for the remaining 24 weeks.

The primary aim of the study was to compare the proportion of patients who received once-daily and twice-daily Kaletra who had a viral load below 200 copies/ml at 48 weeks – what the investigators called a “sustained virological response”. Virological failure was defined as two consecutive viral load measurements above 200 copies/ml, and the final results were calculated in terms of the odds of sustained virological response rather than the percentages with undetectable viral load. The investigators also analysed the effect of directly observed therapy on treatment response.

Over three quarters of the patients were male, and 67% were Hispanic or black. Median baseline CD4 cell count was 197 cells/mm3, the level at which current treatment guidelines suggest that antiretroviral therapy should be initiated. Median viral load at baseline was approximately 50,000 copies/ml.

The study was completed by 82% of patients and 71% remained on their original dose of Kaletra.

Overall, there was no difference in the probability of achieving a viral load below 200 copies/ml between the once-daily and twice-daily arms of the study. However, when the investigators took baseline viral load into consideration, they found that a significantly higher proportion of patients with a higher baseline viral load who received twice-daily therapy achieved a viral load below 200 copies/ml than did patients with higher baseline viral load who received once-daily Kaletra (a difference of 0.13, p = 0.038).

The investigators then analysed the effect of directly observed therapy on treatment outcome. During the period of directly observed therapy, patients receiving once-daily Kaletra via directly observed therapy had a higher probability of experiencing a fall in their viral load to below 200 copies/ml (p=0.07), but this advantage disappeared once the directly observed therapy phase ended.

Discussing the results, Robert Gross of the University of Pennsylvania Medical School highlighted the fact that the ACTG study was larger than a previous manufacturer-sponsored study, and therefore better able to detect differences between the baseline viral load strata. This study, Gross noted, had more than two and half times the number of patients in the higher viral load group.

References

Mildvan D et al. Randomised comparison in treatment-naïve patients of once-daily vs twice-daily lopinavir/ritonavir-based ART and comparison of once-daily self-administered vs directly observed therapy. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 138, 28th February, 2007