As NNRTI-based HAART regimen is extensively prescribed in many resource-limited countries and due to delayed detection of virological failure from lacking the effective monitoring tools and/or inadequate infrastructure in the real-life practice, extensive NRTI and NNRTI-associated mutations could be problematic in those area. To the best of our knowledge, this is the first clinical trial that has shown clinical outcome and pharmacokinetic measures of ritonavir-boosted lopinavir together for the patients experienced with NRTIs and NNRTIs although it was conducted in a small study. Our data indicate that ritonavir-boosted lopinavir monotherapy combined with recycled lamivudine can maintain virological suppression in a substantial proportion of patients who were failing NNRTI-based regimens with M184V, TAMs and NNRTI mutations but were naïve to protease inhibitor. Using intend-to-treat analysis, 60% of patients reached the virological success, i.e., plasma HIV-1 RNA <50 copies/mL, after 48 weeks of treatment. This result is relatively consistent with a recent report that involved antiretroviral-naïve patients by Delfraissy and colleagues . Of 84 patients in ritonavir-boosted lopinavir monotherapy arm, 67% and 79% had achieved undetectable plasma HIV-1 RNA by intend-to-treat and as-treated analysis, respectively. In addition, Gathe and colleagues also reported 77% of antiretroviral naïve patients who were received treatment with ritonavir-boosted lopinavir had undetectable plasma HIV-1 RNA . Regarding immunological response, a higher CD4 cell count while receiving antiretroviral treatment gained, a lower risk for AIDS-related events was associated [12, 13]. The present study reveals that ritonavir-boosted lopinavir showed a great performance on the immunological response after 48 weeks of treatment. A previous study showed that a regimen of ritonavir-boosted lopinavir plus 2 NNRTIs had a greater CD4 cell count response when compared with efavirenz plus 2 NRTIs .
Interestingly, 15% of our patients had low level viremia. This number is considered to be a significant proportion. Of this proportion, 5% achieved undetectable plasma HIV-1 RNA and 10% still had low level viremia at 72 weeks (data not shown). One possible explanation is the lack of viral suppression in some compartments, such as genital secretion and cerebrospinal fluid . Another previous proposed explanation is an alternative pathway of protease inhibitor resistance facilitated by the absence of the NRTI drugs, different HIV subtypes influence on polymorphisms, and a non-adherence issue [16, 17]. There was an increasing risk for virological failure in patients with suboptimal adherence. The current guidelines from Department of Health and Human Services (DHHS) suggested minimum target for lopinavir at >1 mg/L . Therefore, almost all of our patients had their minimum concentration levels exceed the target cut-off value. However, a single therapeutic drug monitoring cannot exclude non-adherence, long-term follow-up is therefore warranted.
Regarding adverse reactions, the most commonly reported side effect associated with lopinavir/ritonavir is mild to moderate diarrhea [18, 19]. In addition, nausea and vomiting, changes in blood lipid levels, elevated transaminase levels and altered blood glucose profiles also have been widely reported . One of our patients needed to discontinue ritonavir-boosted lopinavir due to gastro-intestinal adverse event. Lopinavir/ritonavir soft gel capsules had been used in the present study instead of new lopinavir/ritonavir tablet because tablet formulation had not been available in the country during the study period. The lopinavir/ritonavir tablet formulation could lower the rate of adverse gastro-intestinal symptoms associated with the soft-gel capsules. Although this study was not designed to directly assess metabolic complication, it could revealed a great impact of ritonavir-boosted lopinavir on serum lipid parameters, included total cholesterol, LDL-cholesterol, triglyceride and total cholesterol to HDL-cholesterol ratio, at 48 weeks of treatment. Likewise, a proportion of patients had total cholesterol to HDL-cholesterol ratio above cut-off value; i.e. ≥4, that related to high risk of coronary heart disease [20, 21].
In treatment-experienced patients failing NNRTI-based regimens with limited NRTI options, switching to at least 2 fully active drugs to an optimized antiretroviral regimen is principally the best strategy so far. In patients with earlier first-line treatment failure and have developed either only M184V or with few TAMs, the option of NRTI backbone is still not limited. In these cases, there is a possibility to include 1 or 2 active NRTI drugs in combination with a new drug class, such as PIs, to assure the effectiveness of the regimen. Thus in settings where other new ARV classes beside PIs cannot be assessable, early detect virological failure is crucial to preserve the NRTI backbone. While waiting for a randomized control trial to prove HIV monotherapy with ritonavir-boosted protease inhibitor in these particular patients, the present data provide support to physicians currently facing choices of salvage regimen options in many resource-constrained countries. Ritonavir-boosted lopinavir combined with recycled lamivudine to decrease viral fitness can maintain virological suppression in a substantial proportion of patients failing NRTI and NNRTI with M184V and provides adequate plasma concentrations of lopinavir although incidence of low-level viremia is relatively high. A further larger study would be required to assess the risk and benefit of this proposed strategic treatment in the resource-constrained settings.