Highly active antiretroviral therapy (HAART) has made a significant impact on the natural history of HIV-1 infection, but the toxicities and complexities of therapy limit long-term efficacy, and make simpler yet effective HAART regimens highly desirable. Previous attempts to ‘de-intensify’ protease inhibitor (PI)-based therapy by discontinuing reverse transcriptase inhibitors (RTI) after achieving viral suppression met with failure [1,2], probably because plasma levels of most individually administered PI are too low to inhibit viral replication consistently .
Low-dose ritonavir substantially enhances lopinavir plasma levels , and lopinavir/ritonavir (LPV/r) is effective as part of combination therapy in both naive and PI-experienced patients [5,6]. Furthermore, lopinavir is known to have a high genetic barrier to the selection of resistance [7,8]. LPV/r monotherapy could thus have the right combination of potency, favorable pharmacokinetics, and high genetic barrier needed to suppress viral replication and prevent the selection of lopinavir resistance. This small pilot study explored whether maintenance monotherapy with LPV/r maintains viral suppression once the latter has been achieved with conventional HAART.
Six previously naive patients on therapy with LPV/r 400/100 mg, zidovudine 300 mg, and lamivudine 150 mg given twice a day for at least 24 weeks with the three most recent viral RNA levels at a value of less than 50 copies/ml were identified. Treatment with zidovudine/lamivudine was discontinued; treatment with LPV/r was continued with weekly follow-up for the first 8 weeks, every other week for the next 8 weeks, and subsequently every 4 weeks for the remaining 24 weeks of LPV/r monotherapy. Plasma samples with viral RNA levels of 1000 copies/ml or greater underwent genotypic testing. The results were compared with those of a baseline genotype obtained before the initiation of LPV/r/zidovudine/lamivudine. All baseline genotypes showed susceptibility to all PI and nucleoside RTI.
Responses to maintenance monotherapy (Fig. 1) could be characterized as one of two patterns. Patients 1, 2, 4, and 5 maintained viral RNA levels of less than 1000 copies/ml at all times. Of these four patients, viral RNA values were less than 400 copies/ml on 50 out of 53 occasions (94%) and less than 50 copies/ml on 36 out of 53 occasions (68%).
Patients 3 and 6 had less consistent viral RNA suppression with viral RNA levels of 1000 copies/ml or greater at least once. Both patients acknowledged poor adherence to medications throughout this time. Patient 3 had genotypic testing performed at weeks 4, 5, 10, 12, and 14. None of the protease substitutions associated with decreased susceptibility to lopinavir  were identified at any time; the same polymorphisms present at baseline (L63S and V77I) were detected on most occasions. As adherence to therapy improved after repeated counseling, the last three viral RNA values were all less than 400 copies/ml. Patient 6 had genotypic testing performed at week 24; only the reverse transcriptase and protease polymorphisms present at baseline were detected.
An early indinavir study demonstrated that approximately 40% of patients treated with indinavir monotherapy had viral RNA levels less than 500 copies/ml at 24 weeks of therapy . More recently, a regimen consisting solely of ritonavir-boosted indinavir has been shown to maintain viral suppression after the discontinuation of RTI in patients whose viral load was undetectable on the RTI/PI combination . Preliminary reports have suggested that ritonavir-boosted lopinavir is also able to maintain viral suppression after viral suppression is initially achieved in combination with RTI [11,12]. Furthermore, LPV/r monotherapy dosed by body weight has also been shown to suppress viral replication to less than 50 copies/ml for up to 48 weeks .
This study further demonstrates, albeit in a small number of patients, that LPV/r monotherapy maintained viral suppression in most patients for up to 6 months after viral RNA was suppressed with combination HAART. It is possible that more viral ‘blips’ may have been apparent as a result of the use of more rigorous viral RNA follow-up than is typically employed in clinical practice (e.g. every 3 months). The one patient with sustained viral breakthrough acknowledged intermittent adherence to therapy but a viral RNA level of less than 400 copies/ml was achieved as adherence improved. The two patients with viral RNA levels greater than 1000 copies/ml when on LPV/r monotherapy did not develop detectable resistance to lopinavir.
These findings in combination with previously reported results [10–13] are encouraging. They suggest that successful therapy of HIV-1 infection is possible with more simple regimens. Since the mid-1990s, the simultaneous use of three agents has been and continues to be the standard of care for the treatment of HIV-1 infection [14,15]. However, more potent antiretroviral agents may obviate the need for three active drugs for all patients. Obviously, large, prospective, and controlled studies are needed to investigate this and are, in fact, ongoing (S. Brun, Abbott Laboratories, personal communication). The potential for a significant paradigm shift in antiretroviral therapy exists and is certainly worth exploring.
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