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Intensifying Therapy: Is There a Paradigm?
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written by Michael Kozal, M.D.
published on HIVresistanceWeb: September 25, 1998
I was recently asked by my colleagues and I.D. fellows to describe an antiretroviral treatment intensification paradigm to follow for patients who have HIV RNA levels of <400 copies/mL (by standard PCR testing) but >50 copies/mL (by ultrasensitive PCR). Before answering, I considered the definition of "paradigm". According to Webster's dictionary and Dr. James Armitage (whose lecture on oncology paradigms I recently attended) a paradigm is "an outstandingly clear example". Although in the practice of medicine we desire paradigms to provide direction, we rarely have all the data necessary to construct such a clear path. This is especially true in the HIV field with respect to viral load monitoring, antiretroviral treatment and intensification of therapy. But what do we know? and what might be a reasonable starting point for constructing such a paradigm?
In recent articles on this site, Dr. Bruce Polsky described data showing that despite prolonged suppression of HIV RNA to "undetectable" levels, many patients still show evidence of low level viral replication and development of drug resistance mutations. INCAS data presented by Julio Montaner at the 12th World AIDS Conference in Geneva demonstrated that patients with HIV RNA levels <20 copies/mL were able to sustain a virologic response longer than those patients with <400 but >20 copies/mL. [1] It appears, however, that some patients with <20 copies/mL can still develop drug resistance mutations. At the 2nd International Workshop on HIV Drug Resistance and Treatment Strategies in Lake Maggiore, Italy, Jan van Lunzen and Miguel-Angel Martinez reported that some patients with viral loads <20 copies/mL have evidence of continued HIV replication and evolutionary changes. [2,3] At that same meeting, however, a ray of hope was suggested by data presented by Joseph Wong who described patients with HIV RNA <50 copies/mL who were on potent antiretroviral therapy with 2 RTIs + a PI. Analysis of the env and pol genes of HIV isolated from these patients demonstrated no evidence of ongoing viral replication. [4]
Although it is uncertain whether intensification would benefit the patient with <50 or <20 copies HIV RNA/mL, it is likely that it would benefit the patient who does not achieve or maintain "undetectable" viral loads following initiation of potent antiretroviral therapy. Seventy-two week data from a trial of ritonavir+saquinavir therapy in PI-naïve patients, reported in Geneva by John Mellors, revealed that a majority of patients who still had viral loads of >200 copies/mL or who experienced viral rebound after 12 weeks of dual PI therapy could attain undetectable viral loads by intensifying their regimen with the addition of 2 RTIs. [5] This intensification has been durable, with 78% (21/27) of patients remaining undetectable at week 72 of the trial. These data suggest that patients initiated on a new potent regimen who have their viral loads checked often and early (at week 12 into therapy) can benefit from intensification of their drug regimens. But what about patients who do not have drugs for which they are naïve? The answer in my mind is unclear.
A recent article by Delwart et al has also made me think about the "Intensification Paradigm". Delwart and colleagues studied the effects of PI monotherapy on the diversity of the HIV-1 env locus. [6] By studying the changes in env diversity after starting patients on either nelfinavir or ritonavir, the researchers found that under treatment pressure the initially escaping HIV variants detected came from previously rare env variants (not from the dominant variants seen in plasma), and in some patients minor plasma HIV variants were lost. The authors found that once these PI-resistant and rare env variants emerged, their diversity rapidly (within days to weeks) changed back to the pretreatment env locus type. This phenomenon is likely the result of immune selective forces which may allow these new drug-resistant viruses to recolonize the major drug-susceptible sites of virus production. The authors offered two explanations for their observations: (1) with PI treatment, the virus that escapes drug pressure may arise from PI drug privileged sites (sites where PI activity is reduced), and/or (2) the drug-resistant HIV lineages that emerge arise from a small number of variants (thus the diversity of env variants are decreased—a result of genetic bottlenecking). The authors commented that their data may support the theory that the actual effective HIV-1 population size which perpetuates HIV-1 infection in vivo is smaller than that predicted by a deterministic model of HIV-1 genetic diversity (which dictates a larger effective population size). If this is true an intensification strategy might have a chance to work.
What do these reports teach us about which questions need to be answered and which tools we need before we can start to develop an intensification paradigm? (1) If a patient has <50 copies HIV RNA/mL should we be screening for <20 copies/mL? Or if greatest sensitivity is the goal in this situation, should we discard the quantitative assay in favor of the most sensitive qualitative assay? (2) The rapid re-establishment of dominant env variants in a matter of days to weeks after viral rebound suggests our window of opportunity to intensify therapy is very short. Thus, if we want to devise the best protocol for intensifying therapy we will need to step up the frequency of viral load monitoring (every 3 months or at 4-6 months after starting a new Rx would not be sufficient). (3) In the best of worlds, we could screen escaping virus for drug resistance to determine whether the emerging variants are resistant or are rare variants emerging from drug privileged sites (although in either case the strategy of empirically adding agents could fail because you may add cross resistant agents or those that do not penetrate the site of the emerging population). Right now intensifying the regimen is at best an educated shot in the dark. Not all of us can screen for drug resistance, monitor drug levels, analyze env diversity dynamically (to suggest variants emerging from drug privileged sites), or increase the frequency of viral load monitoring—but maybe we should.
Related HIVresistanceWeb Articles:
Getting a Handle on Cross-Compartmental Viral Replication and Genotypic Resistance
(Bruce Polsky, July/August 1998)
References
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- How low is low enough? Suppression of plasma viral load below 20 copies/mL is necessary for long term virologic response.
Montaner J, Montessori V, Raboud JM, Conway B, Robinson P, Myers M, Hall D. The 12th World AIDS Conference. 28 June-3 July 1998, Geneva, Switzerland. Abstract 12364.
- Persisting HIV-1 replication in lymphoid tissue despite prolonged undetectable levels of viraemia during nucleoside analogue combination therapy compared to protease inhibitor-containing regimens.
van Lunzen J, Ruiz L, Stellbrink HJ, Arno A, Cloter B, Tenner-Racz K, Racz P. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 146.
- HIV-1 genetic evolution in patients with prolonged suppression of plasma viraemia.
Martinez MA , Cabana B, Ibinez A, Arno A, Ruiz L. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 147.
- HIV recovery from PBMC of patients with undetectable plasma viraemia is not due to residual viral replication.
Günthard HF, Ignacio CC, Kee K, Havlir DV, Spina CA, Hezareh M, Richman DD, Wong JK. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 148.
- Ritonavir (RTV)-saquinavir (SQV) in protease inhibitor-naïve patients after 72 weeks.
Mellors J, Japour AJ, Leonard J, Sun E, Xu Y, Salgo M. M97-462 Study Groups. The 12th World AIDS Conference. 28 June-3 July 1998, Geneva, Switzerland. Abstract 12295.
- Rapid, transient changes at the env locus of plasma human immunodeficiency virus type 1 populations during the emergence of protease inhibitor resistance.
Delwart EL, Pan H, Neumann A, Markowitz M. J Virol. 1998 Mar;72(3):2416-21.
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