Schechter.fm

Monotherapy with
lopinavir/ritonavir
Mauro Schechter† & Estevão Portela Nunes †Projeto Praça Onze, Universidade Federal do Rio de Janeiro, Brazil Despite the unprecedented pace of development of drugs for the treatment of a viral disease and the unquestionable efficacy of antiretroviral therapy, there is a need for less toxic and cheaper regimens that could simplify the treatment of HIV infection without sacrificing efficacy. The favorable pharmacokinetic profile and the high genetic barrier of boosted protease inhibitors make them ideal candidates for use as monotherapy. Given the encouraging results of available studies on lopinavir/ritonavir monotherapyin patients with no prior failure with protease inhibitors, it may be warranted to conduct trials to investigate the cost-effectiveness of lopinavir/ritonavirmonotherapy as second-line therapy in resource-constrained settings wherevirologic monitoring is not feasible. In addition, larger trials with longer fol-low up, with particular attention to the potential consequences of viral repli-cation in sites where the penetration of protease inhibitors may be poor, areneeded before this strategy can be considered for routine use.
Keywords: HAART, HIV treatment, induction–maintenance, lopinavir/ritonavir,
protease inhibitors
Expert Opin. Investig. Drugs (2007) 16(5):735-741
1. Introduction
In the 25 years that have elapsed since the description of the first cases, AIDS hasbecome, on a global scale, one of the major challenges that healthcare systems haveto contend with. The effect of the HIV pandemic is particularly severe in developingcountries, where the growing number of infected individuals exerts increasingpressure on already overstretched and under-funded health services. The addedstress to healthcare systems has particularly affected hospital medical wards. Forexample, HIV-infected patients have been reported to constitute 52 and 70% ofmedical admissions to hospitals in Uganda and Malawi, respectively, and 80% oftuberculosis admissions to a large hospital in South Africa [1-3].
In 1987, < 4 years after HIV-1 was identified, zidovudine (AZT; a nucleoside reverse transcriptase inhibitor [NRTI]) became the first approved drug for the treat-ment of individuals with AIDS or with advanced HIV-induced immunodeficiency.
In the ensuing years, other NRTIs were approved for clinical use. In 1995, theextraordinary effect of a new class of drugs (i.e., the protease inhibitors [PIs]) on theprognosis of patients with advanced HIV disease led to profound changes in treat-ment paradigms. A third class of antiretroviral drugs, the non-NRTIs, becameavailable in 1998. Concurrently, clinical trials data – coupled with a better understanding of the dynamics of HIV replication and of drug-resistance mechanisms – led to triple-drugcombination therapy, the so-called highly active antiretroviral therapy (HAART),becoming the standard of care in developed countries. HAART was shown to lead tosuppression of viral replication to levels below the limits of detection with com-mercially available assays in virtually all treatment-naive patients who succeeded tocomply with the prescribed regimens. It was also shown that HAART limits thedevelopment of drug resistance by several mechanisms, including the increase in the 10.1517/13543784.16.5.735 2007 Informa UK Ltd ISSN 1354-3784 Lopinavir/ritonavir
so-called genetic barrier (i.e., the number of mutations that in which some, but not all, agents are stopped (the HIV has to accumulate to become resistant to a particular antiretroviral drug or combination of drugs).
Initial studies that used the induction–maintenance In the developed world, the rapid introduction and wide- strategy produced disappointing results, with high failure spread use of HAART led to dramatic changes in morbidity rates in patients randomized to the maintenance phase with and mortality associated with HIV infection [4]. However, fewer drugs [13,14]. The best-known example of these early care for HIV-infected individuals in developing countries was studies was probably the study called ACTG-343. In this ran- initially limited to chemoprophylaxis and treatment of certain domized trial, patients with plasma viral load < 200 copies/ml opportunistic infections, and excluded treatment of HIV itself for 6 months on indinavir plus zidovudine and lamivudine with antiretroviral drugs, which were considered to be were randomized to remain on the 3-drug regimen or switch unaffordable. However, in the last few years, price reductions to indinavir alone or to the 2 NRTIs alone. The three-drug of branded drugs and increasing competition from cheaper arm outperformed the other two arms, using virologic failure generic formulations has substantially decreased the cost of as the main outcome measure. High viral load at the initiation antiretroviral drugs, thereby increasing the feasibility of their of the induction phase was a predictor of failure, suggesting use in resource-poor settings. In March 2004, the United that the regimens used may not have been potent enough or Nations General Assembly declared that the failure to deliver that the induction phase may not have been long enough to antiretroviral treatment for HIV/AIDS was a global health achieve effective induction. Interestingly, it was also shown emergency. In September 2005, at the World Summit of the that virologic failure in the group treated with indinavir United Nations, Heads of State called for universal access to monotherapy was related to low plasma drug concentrations, HIV treatment by 2010. Data from a variety of settings have not to the development of genotypic resistance [15].
demonstrated that adherence in developing countries may be Soon after the results of ACTG-343 were published, as good as, or even better than, in developed countries [5] and Gisolf et al. [16] reported good laboratory responses in that antiretroviral therapy is as effective in developing antiretroviral-naive patients on full-dose therapy with the countries as it is in the developed world [6,7], having a similar two PIs ritonavir and saquinavir, without a NRTI. A total of effect on morbidity, mortality and the use of healthcare 63 and 88% of the patients achieved virologic suppression and < 400 copies/ml on week 48, on intention-to-treat andon-treatment analyses, respectively. Although the relevance 2. Early studies
of full-dose ritonavir in this combination has been ques-tioned, the results of this trial and of ACTG-343 provided Over the last years, several limitations of antiretroviral evidence to indicate that the potential effectiveness of regi- therapy have become increasingly evident. These include data mens containing only PIs could not be ruled out given to indicate that virologic failure rates may be substantially higher in clinical practice than in clinical trials [9], the Ritonavir is a PI that is poorly tolerated if given at full dose.
appreciation of the difficulties associated with long-term It is a potent inhibitor of CYP3A and CYP2D6, as well as an adherence to complex regimens and concerns about the inducer of other hepatic enzyme systems. Thus co-admin- long-term safety of antiretroviral drugs and their effect on istering ritonavir with drugs that are metabolized through quality of life [10-12]. Another cause for concern is the large hepatic enzyme systems (such as most PIs) causes clinically and increasing number of HIV-infected individuals who live significant alterations in serum levels of the latter, leading to in developing countries, which has led to doubts about the substantial enhancement of drug exposure. As a consequence, long-term financial and logistical sustainability of large-scale ritonavir boosting results in improved drug levels that can treatment programs in resource-constrained settings. Thus increase efficacy, decrease pill burden, add flexibility to the there is a need for simpler, less toxic and more inexpensive dosing schedule and remove fasting restrictions for many PIs.
treatment regimens despite the unprecedented pace of devel- These improved pharmacokinetic characteristics have led to opment of drugs for the treatment of a viral disease and the most licensed PIs being presently given in the boosted form, unquestionable efficacy of HAART. Not surprisingly, discus- as well as leading to a renewed interest in the use of boosted sions have arisen on strategies to simplify antiretroviral PIs in induction–maintenance strategies. therapy without sacrificing efficacy.
Boosted indinavir, lopinavir and atazanavir have been Successful precedents in cancer chemotherapy have led to studied in trials of maintenance monotherapy. Because of its suggestions that induction–maintenance strategies may toxicity, boosted indinavir is no longer in widespread use.
simplify antiretroviral therapy, decrease treatment-relatedadverse effects and reduce long-term costs, as well as provide 3. Lopinavir/ritonavir monotherapy studies
adequate control of viral replication. Under this approach,treatment would be initiated with a highly potent regimen Lopinavir/ritonavir (LPV/r) has been evaluated in at least four that is continued until HIV replication in the plasma is no maintenance trials [17-20]. Data on atazanavir/ritonavir longer detectable (the induction phase) followed by a phase (ATV/r) monotherapy are more limited [21,22]. It was recently Expert Opin. Investig. Drugs (2007) 16(5)
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reported that one trial in which ATV/r monotherapy was used (90% efficacy on the as treated analysis) at week 48. Only two in the maintenance phase was prematurely terminated before cases of virologic failure were identified; in both cases, enrollment had been completed because of an unacceptable genotypic tests showed wild-type viruses and the viral load was successfully suppressed following intensification with Co-formulated LPV/r is commercially available. Boosting of lopinavir with low-dose ritonavir leads to several favorable The MONARK (Monotherapy Antiretroviral Kaletra) trial pharmacokinetic characteristics that, coupled with the simple compared LPV/r monotherapy with LPV/r associated with dosing scheme, are associated with a low risk of treatment fail- zidovudine and lamivudine for initial therapy. The study ure due to insufficient blood concentration of the drug, which included 138 patients with a viral load of < 100,000 cop- was the presumed cause for the failure of the indinavir mono- ies/ml and CD4+ cell count of > 100 cells/ml. After 24 weeks therapy arm in ACTG-343. The co-formulation was origi- of follow up, there were no statistically significant differences nally approved for clinical use in soft-gel capsules and in between rates of virologic suppression of < 400 copies/ml.
liquid form. Subsequently, a heat-stable tablet – with the Nonetheless, a larger proportion of patients in the triple-drug potential to greatly improve tolerability and to reduce gastro- therapy group had viral loads of < 50 copies on week 48 (98 intestinal symptoms that are commonly associated with the former presentations – was approved for clinical use. At A total of four randomized maintenance trials (OK study, present, the soft-gel capsule is being phased out. LPV/r is OK-04 study, study M03-613 and the KalMo study) have approved for twice-daily dosing; it is also approved for evaluated and compared LPV/r monotherapy with standard once-daily dosing in treatment-naive adults. One of the main triple-drug regimens. The OK study [17] included 42 patients advantages of LPV/r for use as monotherapy is that patients who had been on LPV/r plus 2 NRTIs for ≥ 1 month, had cannot fail to take one component of the regimen due to the maintained a HIV plasma viral load of < 50 copies/ml for co-formulation, which can be hazardous in individuals receiv- > 6 months and had no history of virologic failure during ing ritonavir-boosted monotherapy. This is because taking treatment with a PI. Participants were randomly assigned to either ritonavir alone or the active PI without ritonavir may maintain their present regimen (control group) or to stop the increase the risk of viral rebound and PI resistance due to NRTIs (OK group). The primary study outcome was the inadequate concentrations to maintain viral suppression.
proportion of patients with < 500 copies/ml at 48 weeks. On Another potential advantage of LPV/r is the high genetic bar- intent-to-treat analysis, there were no significant differences in rier to resistance, multiple mutations being necessary before a the proportion of participants with plasma viral load of high level of clinically relevant resistance develops [24]. The < 500 copies/ml (81 and 95% in the OK and control groups, selection of resistance to LPV/r in treatment-naive patients respectively; p = non-significant) at 48 weeks. All patients seems to be rare [25]. In fact, in clinical trials of treat- who achieved a plasma viral load of < 500 copies/ml at week ment-naive patients who experienced virologic failure, very 48 were also below the detection limit using the assay for few cases of genotypic or phenotypic resistance to LPV/r have < 50 copies/ml. Of the 21 patients who were assigned to the so far been described. On the other hand, resistance to LPV/r monotherapy arm, 3 had a loss of virologic suppression has been noted to emerge in patients who have previously defined as 2 consecutive measures of > 500 copies/ml 2 weeks failed other PIs and who experienced virologic failure during apart; 1 patient discontinued treatment after a first result showed > 500 copies/ml and was subsequently lost to follow Because of its intrinsic potency and high genetic barrier, up. The analysis of adherence by drug refill showed that these LPV/r was a natural candidate for monotherapy trials. Initial patients had a significantly higher number of total days studies included a group of patients that were randomized to without medication and total missed doses on the week prior use LPV/r monotherapy for the first 2 weeks of a Phase II to each visit. None of the viruses isolated at viral rebound in trial. The slope of viral load decline in this group was similar the OK group had primary-site or active-site mutations in the to the slope that was observed in the group randomized to the protease gene by standard genotyping. The two participants triple-drug therapy [27]. In another study (a cohort of who experienced viral rebound during treatment 15 patients who were considered to have no other option but (monotherapy) and who remained in the study were to use LPV/r monotherapy due to toxicity, intolerance or successfully re-suppressed with the re-introduction of the resistance to other classes of antiretroviral drugs) were fol- lowed. After a mean follow up of 82 weeks (range: 57 – 122), The eligibility criteria for the OK-04 study [18] were essen- 11 of the 15 patients succeeded to suppress viral load to tially the same as for the OK study [17]. The primary end < 75 copies/ml [28]. Gathe et al. [29] conducted a non-com- point was the proportion of participants without therapeutic parative trial of LPV/r monotherapy as an initial therapy that failure at 48 weeks. Therapeutic failure was defined as involved 30 patients. Although there was a high number of 2 measurements of plasma viral load of > 500 copies/ml discontinuations for reasons other than virologic failure 2 weeks apart. An extremely important feature of this trial (particularly non-adherence and loss to follow up), there were was that intensification with NRTIs was permitted in the 18 participants with plasma viral load of < 50 copies/ml LPV/r monotherapy arm if virologic rebound occurred.
Expert Opin. Investig. Drugs (2007) 16(5)
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These were not considered to be therapeutic failures if, after virologic failure being defined as a confirmed HIV-1 RNA of the re-introduction of the NRTIs, viral load decreased > 1000 copies/ml. Results of an interim analysis at 48 weeks > 1 log10 copies/ml by 4 weeks after re-intensification and to have been presented and no significant differences were < 50 copies/ml by 16 weeks after re-intensification. Thus the identified between the 2 groups with regards to the primary main outcome comparison between the two arms was viro- outcome: by intent-to-treat analysis, 26 out of 30 (86.7%) of logic failure during treatment with HAART. There were the patients in the monotherapy arm and 25 out of 30 103 patients who were randomized to the monotherapy arm (83.3%) of the patients in the control arm had plasma viral and 102 to the control group. At week 48, the proportion of load < 80 copies/ml. Only one patient on LPV/r patients without therapeutic failure was 94.0 and 89.8% in monotherapy reached the defined criteria for virologic failure.
the monotherapy arm and in the control arm, respectively Genotypic testing was performed and no relevant mutations were found. The nucleoside backbone was re-introduced and Study M03-613 [19] was an open-label, randomized and the viral load was < 80 copies/ml after 4 weeks. Apart from controlled trial that compared switching to LPV/r mainte- this case, there was just 1 patient who presented low-level nance monotherapy with continued treatment with efavirenz viremia (80 – 1000 copies/ml) between weeks 24 and 48. At plus two NRTIs in treatment-naive patients. The comparator 96 weeks, viral load was again < 80 copies/ml during arm was chosen based on the fact that efavirenz-based regi- treatment with monotherapy (manuscript in preparation).
mens are the most commonly prescribed regimens for initialtherapy in developed countries. The inclusion criteria were 4. Other trials and future directions
being antiretroviral naive and to have a plasma viral load of> 1000 copies/ml. Eligible patients were randomized to start The encouraging results of pilot studies with PI-boosted zidovudine plus lamivudine plus efavirenz (the control arm; monotherapy led to a growing interest in trials involving other n = 51) or to zidovudine plus lamivudine plus LPV/r PIs, particularly atazanavir, which can be dosed once daily, has (n = 104). According to the protocol, patients in the latter a more favorable lipid profile and also a better gastrointestinal arm who achieved a plasma viral load of < 50 copies/ml for tolerance. Although this strategy seemed to be effective and 3 consecutive months (during months 3 – 11 of the study) well tolerated in two small, non-comparative studies involving should discontinue zidovudine plus lamivudine. The primary maintenance therapy [21,22], it was recently reported that one outcome was the proportion of patients with plasma viral load trial in which ATV/r monotherapy was used in the main- of < 50 copies/ml at week 96. A total of 92 out of 104 subjects tenance phase was prematurely terminated before enrollment (88%) receiving LPV/r plus zidovudine/lamivudine induction had been completed because of an unacceptable rate of therapy met protocol-defined criteria for switching to main- virologic failure [23]. This trial included patients on HAART tenance monotherapy with LPV/r. By intent-to-treat analysis, with no prior PI therapy who had a HIV RNA viral load of the primary outcome was not significantly different in the two < 20 copies for ≥ 12 months. Despite the use of therapeutic study arms. Low-level viremia (HIV-1 RNA of > 50 copies/ml drug monitoring to adjust the dose of atazanavir, there were but < 500 copies/ml) was more frequent in the monotherapy 5 cases of protocol-defined virologic failure at a time when arm, but most participants regained viral suppression in only 15 of the planned 30 patients had been recruited.
follow-up assessments after re-intensification with zidovudine Pharmacokinetic analysis did not differ between patients with and lamivudine (2 out of 4 patients) or even when continuing or without virologic failure, although two of the patients who on LPV/r monotherapy (11 out of 12 patients). Among the experienced virologic failure had used acid-suppressing drugs 15 patients on monotherapy with loss of virologic control for that are known to interact with atazanavir, which were pro- whom genotypic tests were performed, 2 developed resistance hibited by the study protocol. Of note, bilirubin con- mutations in the protease gene that were not present on centrations recorded during treatment were significantly baseline samples, 1 of them was during the triple-drug induc- lower in patients with virologic failure. As this side effect may tion phase. DEXA (dual-energy X-ray absorptiometry) scans be related to the intracellular concentration of the drug, where demonstrated that peripheral lipoatrophy (defined as > 20% it exerts its activity as a PI, the authors speculated that a decrease in limb fat mass) was significantly more common in low-serum bilirubin level may be a marker for a low the efavirenz plus AZT plus lamivudine arm than in the LPV/r monotherapy group (34 versus 5%; p < 0.001) [31].
The recently published results on monotherapy with The KalMo (Kaletra Monotherapy) study [20] was also an boosted atazanavir should add a note of caution to the notion open-label study in which 60 patients with a plasma viral load that boosted monotherapy with all PIs should be equally of < 80 copies/ml for ≥ 6 months on the present HAART reg- effective. In addition, there are others concerns involving imen, with no prior virologic failure, with a present CD4+ cell PI-boosted monotherapy. There are few data on how viral count of > 200 cells/ml and a nadir of CD4+ cell count of replication in sites other than plasma is affected by PI-boosted > 100 cells/ml, were randomized 1:1 to maintain their present monotherapy. Available data indicate that PIs concentrate regimen or to switch to LPV/r monotherapy. The primary poorly in certain sites, such as the cerebrospinal fluid and end point was HIV-1 RNA of < 80 copies/ml by week 96, genital secretions. In turn, this may affect viral replication in Expert Opin. Investig. Drugs (2007) 16(5)
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the CNS, with unknown consequences, as well as sexual intra-class cross-resistance is relatively common and thus can transmission. In fact, suboptimal suppression of viral limit treatment options for those who fail or who are intoler- replication in the cerebrospinal fluid has been demonstrated ant to their prescribed regimen; and the long-term safety of with the use of ritonavir/saquinavir [32] or of boosted atazana- many drugs used at present is a matter of concern. Data that vir without the NRTI backbone [23]. The presence of drug lev- indicate that some of the toxicities associated with the els below the therapeutic range in these so-called sanctuary long-term use of NRTIs (such as lipoatrophy and peripheral sites may also select resistance mutations. Data from neuropathy) may not be fully reversible are particularly MONARK [33] and MO3-613 [34] showed virologic sup- troublesome. Accordingly, there is a need for simple and less pression with boosted lopinavir monotherapy in semen and toxic regimens, particularly nucleoside-sparing regimens the cerebrospinal fluid despite poor lopinavir concentration in that could simplify therapy without sacrificing efficacy. One both sites; the sample size was small in both cases. Future of the proposed strategies to achieve these goals is to initiate trials will also have to examine the importance of transmitted treatment with a highly potent regimen for a period of time primary resistance in naive patients, which could potentially (the induction phase) followed by a phase in which the reduce the genetic barrier and increase the risk of virologic NRTI backbone is stopped (the maintenance phase). The favorable pharmacokinetic profile and the high genetic bar- It is expected that simplification strategies that allow the rier of boosted PIs make them ideal candidates for use as use of a single agent may improve adherence. However, it could be easier for many patients to adhere to regimens that In accordance with WHO recommendations [35], the vast involve the use of multiple drugs that are co-formulated, have majority of patients in developing countries are started on reg- a lower pill burden, can be dosed once daily and/or are associ- imens that include two NRTIs and one non-NRTI. Given its ated with less gastrointestinal symptoms than boosted PIs.
high cost and technologic complexity, viral load monitoring is The studies reviewed in this paper used the soft-gel formula- still not widely used in most resource-constrained settings.
tion of LPV/r. It remains to be determined how the recently Hence, first-line regimen failure in these settings is often available tablet formulation (which is better tolerated, does defined on clinical and/or immunologic grounds, which tend not have food restrictions and has a reduced pill burden) will to occur long after virologic failure. As a consequence, multi- ple resistance mutations are likely to have accumulated by thetime therapy is changed and the efficacy of other potential 5. Conclusions
NRTI backbones will have been severely compromised. Giventhe encouraging results of available studies with LPV/r mono- In 4 prospective randomized trials that involved > 400 partic- therapy in PI-naive patients, trials are warranted to investigate ipants who were followed for 48 – 96 weeks, LPV/r main- the cost-effectiveness of LPV/r monotherapy as a second-line tenance monotherapy has been shown to have an efficacy that therapy in resource-constrained settings where virologic mon- is similar to standard triple-drug therapy. Despite rebound itoring is not feasible. In addition, larger trials of mono- viremia, which is typically of low-level viremia (i.e., > 50 but therapy using lopinavir tablets that could also provide < 500 copies/ml), being generally more common with this definitive data on the consequences of viral replication in strategy compared with remaining on HAART, development sanctuaries, as well as longer follow up, are needed before this of resistance mutations seems to be rare and re-suppression strategy can be considered for routine use.
with the re-introduction of the NRTIs was almost universallyachieved. However, recent data on ATV/r monotherapy have Disclosure
raised concerns regarding the efficacy of this strategy,particularly when other PIs are used.
M Schechter has received research grants from AbbottPharmaceuticals; Boehringer Ingelheim; Bristol-Myers 6. Expert opinion
Squibb; Gilead Sciences; GlaxoSmithKline; Merck; Pfizer,Inc.; Roche; and Tibotec. M Schechter has also participated In the last 10 years, the availability of HAART has trans- on the advisory boards of Abbott, Bristol-Myers Squibb, formed a universally fatal disease into a chronic, manageable condition. Despite this unprecedented success, there is still EP Nunes has received a research grant from Abbott.
considerable room for improvement as: difficulties EP Nunes has also participated on the advisory board of associated with long-term adherence to treatment leads to Abbott. EP Nunes has received lecture fees from Abbott, failure rates still being quite appreciable in clinical practice; United Medical and Bristol-Myers Squibb.
Expert Opin. Investig. Drugs (2007) 16(5)
Lopinavir/ritonavir
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