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Questions and answers from clinical trials of lopinavir/ritonavir monotherapy presented at WAC in Toronto
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Jose R Arribas, MD
Answers:
1. Successful treatment of HIV infection does not always require the use of three drugs. Sometimes the details make us forget about the main research finding. No matter how we look at the data KALMO [1], MONARK [2], M03-613 [3] and OK04 [4] clearly show that LPV/r monotherapy works as initial or as maintenance therapy in a surprisingly high proportion of patients. Even the most skeptical reviewer of these studies has to admit that LPV/r monotherapy has nothing to do with monotherapy using nucleosides, non-nucleosides or unboosted PIs. These four studies clearly challenge the notion that using three drugs is a prerequisite "written in stone" for successful anti-HIV therapy.
2. LPV/r monotherapy does not expose patients to a high risk of developing resistance.
Primary protease inhibitors mutations were detected in 2 out of 83 patients randomized to LPV/r monotherapy in MONARK, in 2 out of 102 in M03-613 and in 2 out of 100 in OK04. Therefore is fair to say that the risk of resistance does not appear to be high in patients who receive LPV/r monotherapy. In fact this prevalence of resistance compares favorably with simplification strategies in which the boosted PI is switched for an NRTI or an NNRTI. Nevertheless, for some reviewers the quick take home message is that in sharp contrast with trials of LPV/r and two nucleosides in na•ve patients we have seen resistance "development" in the monotherapy trials. A closer look at data presented at the Fifteenth HIV Drug Resistance Workshop questions this conclusion:
- In MONARK, two patients developed resistance after 42 and 72 weeks of almost continuous low-level viral replication. [5] It is not at all surprising that HIV evolves towards resistance after such an extended period of uncontrolled viremia. If HIV is allowed to replicate for a very prolonged period of time in the presence of antiretroviral drugs, alone or in a triple combinations. resistance is going to appear. One might argue that if patients are receiving triple therapy with LPV/r and two nucleosides (in general including 3TC or FTC) clinicians could be more inclined to rapidly stop a non-suppressive regimen for the fear of development of M184V and in this way they protect the other components of the regimen. Another important finding from these two patients is that the protease mutations that appeared did not compromise, at all, the whole family of protease inhibitors. In fact LPV/r IC50 did not change significantly by phenotypic test.
- In M03-613 is by no means clear-cut that the 2 patients "developed" PI resistance [6]. Genotypic testing of pre-monotherapy samples clearly suggest that this two patients had been exposed to other antiretrovirals and very likely harbored PI mutations before entering the trial
- In OK04 we found resistance mutations in two patients randomized to the monotherapy arm an in one patient randomized to the triple therapy arm. It should be emphasized that patients included in this trial could have been treated with other PIs before randomization and could have made switches due to toxicity or convenience. Although no history of virological failure while taking a PI was an inclusion criteria we cannot disprove the existence of PI mutations at baseline.
3. LPV/r monotherapy for maintenance of HIV suppression is a strategy than can be safely tried
If a patient has had virolgical suppression for six months and doesnÕt have prior PI mutations the results of the OK04 trial show that a monitored period of LPV/r monotherapy to find out if suppression can be maintained is a feasible clinical strategy. In OK04 only a minority of patients (6 out of 100) had confirmed loss of virological suppression (two viral loads above 500 copies/mL). Of these 6 patients 4 were successfully reinduced with baseline nucleosides. At the end of the trial even with the most stringent analysis (ITT missing data and reinduction = failure), 85% were below 50 copies at 48 weeks while still receiving LPV/r monotherapy. In the OK04 trial patients were seen every three months, which is not far from common clinical, real-life, follow-up. When reviewers analyze the results of LPV/r monotherapy in OK04 some interpret the "failures" of monotherapy as if they were as irreversible as NNRTI or 3TC/FTC failures. In the overwhelming majority of these "failures", the clinical consequence was that patients had to resume the same regimen that they were taking at baseline. This is the essence of the strategy evaluated in OK04: LPV/r monotherapy can be tried, and if it "fails", it is very likely that no options have been lost. By pure intention to treat (arguably the best analysis for evaluating therapeutic strategies) the proportion of patients without theapeutic failure at 48 weeks was higher in the monotherapy group than in the triple therapy group (difference non-statistically significant).
4. The efficacy of LPV/r monotherapy to completely suppress HIV replication below 50 copies/mL depends on the setting in which it is used.
MONARK, M0-613, and OK04 consistently showed that a higher proportion of patients in the LPV/r monotherapy arms experience low-level (between 50 and 500 copies/mL) persistent viral rebound when compared to patients receiving triple therapy. Interestingly this proportion of patients was higher in MONARK (antiretroviral na•ve patients), intermediate in M0-613 (patients stopped the nucleosides after a minimum of three months with viral loads less than 50 copies/mL) and lowest in OK04 (patients stopped the nucleosides after a minimum of six months with viral loads less than 50 copies/mL). It should be noted that in OK04 this event occurred in very few patients (less than 5% of patients). Persistent low-level viremia can be controlled (in the absence of PI mutations) adding-back prior nucleosides. The cause of this viremia is at present unknown.
Questions:
1. What about reservoirs?
One criticism of LPV/r monotherapy is the possible lack of efficacy in protected reservoirs, mainly CNS and the male genital tract. The quick interpretation is that LPV/r does not adequately penetrate the blood-brain and the blood-testis barriers. It is clear that this issue has to be adequately studied. However, there are already data suggesting a significant antiviral activity of LPV/r monotherapy in the CNS [7]. With regard to the male genital tract it also should be remembered that lack of penetration does not immediately means lack of activity [8] and the real relevance of this finding has to be adequately determined. Studies are in progress to clarify this issue.
2. Is LPV/r monotherapy simpler than other regimens?
Obviously not, there are simpler regimens. However there are many patients receiving LPV/r and two nucleosides who cannot be switched to an NNRTI-based regimen for a variety of reasons (CNS side effects, risk of unplanned pregnancy, risk or periods of very poor adherence, already resistant to NNRTIs, etc). Clear examples of this need are two real-life cohorts of patients who were treated with LPV/r monotherapy [9,10] presented also at WAC. In several settings, LPV/r monotherapy could become a simplification option, specially with the new meltrex formulation.
3. What are the benefits of LPV/r monotherapy?.
In most of the world the main barrier for treatment is cost. Having a single-drug antiretroviral treatment which works in a large number of patients would greatly help access to treatment in low and middle income countries. By intention to treat (missing data and reinduction = failure) the proportion of patients with less than 50 copies/mL at 48 weeks was 71% in MONARK and 85% in OK04. This is a very substantial efficacy rate, strikingly different from the result of prior attempts to anti-HIV monotherapy. A detailed pharmacoeconomic analysis has to be performed but is hard to believe that LPV/r monotherapy might not help to decrease the costs of antiretroviral treatment. Another important potential niche for this strategy could be its use after failure of the d4T/3TC/Nevirapine coformulation in the developing world.
Currently most HIV-infected patients face life-long treatment. Nothing is known about the long-term effects (after ten, fifteen years) of what we consider now "safe" drugs. Knowing that we can use less than three drugs for the treatment of HIV adds to our ability to design more flexible regimens and avoid drug exposure.
4. Is LPV/r monotherapy ready for widespread use?
No. Although information is accumulating rapidly (more than 300 patients who receive LPV/r monotherapy in clinical trials were presented at WAC), prudent clinicians would wait until longer follow-up of ongoing trials is available and most of the issues discussed above are clarified.
References
1. Nunes EP, Oliveira MS, Almeida MMTB, et al. 48-week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/mL on HAART--the KalMo study. XVI International AIDS Conference. August 13-18, 2006. Toronto. TUAB0103.
2. Delfraissy J-F, Flandre P, Delaugerre C, et al. MONARK Trial (MONotherapy AntiRetroviral Kaletra): 48-week analysis of lopinavir/ritonavir (LPV/r) monotherapy
compared to LPV/r + zidovudine/lamivudine in antiretroviral-naive patients. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0202.
3. Cameron W, da Silva B, Arribas J, et al. A two-year randomized controlled clinical trial in antiretroviral-na•ve subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0201.
4. Arribas J, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV- viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 study). XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0203.
5. M Norton et al. Drug resistance outcomes in a trial comparing lopinavir/ritonavir (LPV/r) monotherapy to LPV/r + zidovudine/lamivudine (MONARK Trial). Fifteenth HIV Drug Resistance Workshop, Sitges, Spain, abstract 74, 2006.
6. JR Hackett Jr et al. Selection of protease inhibitor (PI) resistance mutations during virological failure of lopinavir/ritonavir (LPV/r) monotherapy in an induction-maintenance study. Fifteenth HIV Drug Resistance Workshop, Sitges, Spain, abstract 75, 2006.
7. G. Van den Brande et al. Kaletra (LPV/r) Independently Reduces HIV Replication in Cerebrospinal Fluid. 12th CROI Š Boston, 22-25 February 2005. Abstract #403.
8. Lowe SH et al. Is the male genital tract really a sanctuary site for HIV? Arguments that it is not. AIDS. 2004;18:1353-62.
9. Waters L, Gazzard B, Bower M, Nelson M. Kaletra monotherapy: a real-life experience. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THPE0132.
10 Goelz J, Wolf E, Moll A, et al. Single agent HAART with lopinavir/r in ART-naive and pre-treated HIV-1-infected patients. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THPE0134.
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