Medical Consultant
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6th Conference on Retroviruses and Opportunistic Infections January 31 - February 4, 1999 - Chicago, IL |
Simon Collins, ATP
Even with the most potent of regimens though there is a proportion of people who do not respond and this incomplete response rate is even more dramatic when looking at patients who have been heavily pre-treated or who start treatment with a high viral load. Current regimens are clearly limited by their complexity, long- and short-term toxicity and cross resistance between drugs of the same class. The success of the next step forward will therefore be dependent on many factors.
Referring to the work of Julio Montaner, Doug Richman and others he stressed that the goal of antiretroviral therapy must recognise the importance of almost complete suppression (< 50 copies/ml on the current ultrasensitive tests). Below this level there is little evidence of continued viral evolution and a greater chance of long-term success. In addition to listing the well known advantages and disadvantages of PI or NNRTI based combinations, Dr Vella touched on two less studied strategies: the possiblities of potent viral suppression with NNRTI's (citing the extended efficacy of efavirenz with high baseline viral loads [4] ), and the potential of triple nucleoside analogue combinations (citing early results from the Atlantic trial [5 & 6].
We have more experience with PIs, they are currently used at all levels of baseline viraemia and can have beneficial PK interactions. Their disadvantages are the complexity of the regimen and implications for adherence, long term side-effects and complexity of cross-resistance.
NNRTI regimens can defer the use of PI and benefit from a low pill burden but are only slowly revealing long-term efficacy, work on a single target and offer far more limited likelihood of a second chance with the class because of high cross-resistance. Triple nucleoside first-line treatment may have long term strategic benefits which balance the single target attack against retaining two unused families for salvage. However, great care must be taken over considering what type of resistance might be seen in patients failing triple NA's and how subsequent classes of agents might be supported in combinations if emergent virus was multiply nucleoside resistant. Differences in long-term outcome between regimens, including constraints on subsequent options and activity in the central lymphoid tissue may not become clear until strategic trials (INITIO in Europe and ACTG 384 in the US) present their first results. Until then physicians have to tread very carefully.
There is also evidence that we may currently be relying too heavily on current regimens whose potency may just not be sufficient:
If the speed of viral clearance is a predictor of sustained suppression - the more potent the regimen, the quicker the viral decline and the longer the regimen could last. This is being studied in ACTG 388 which compares a triple combination to two quadruple arms.
Drug pharmacokinetics may vary widely amongst individual patients being influenced by absorption, gut wall and hepatic metabolism, intracellular uptake and clearance, protein binding renal clearance etc. - drug-level monitoring and dose adjustments may be able to compensate for some variabilities due to these factors. This may, in turn, lead to increases in the overall virological response rates seen in controlled trials. There might, additionally, be residual HIV replication despite full plasma suppression - at least in compartments like the CNS or male and female genital tract where it is difficult for some drugs to penetrate. Dr Vella emphasised that resistance - rather than being a cause for failure in itself - is more often a consequence of inadequate treatment adherence, inadequate drug pharmacokinetics and inadequate drug activity. It was very reassuring in a presentation of this level to hear it stressed that "...the measuring of therapeutic drug levels will become a must'" - standard of care guidelines take note!
Because continuing therapy with low but detectable plasma viremia is associated with gradual emergence of resistance, a strict definition of failure should be a confirmed detectable viral RNA (<50 copies/ml) in a patient who is adherent and who has previously been undetectable (and who hasn't had a recent vaccination or intercurrent illness). In practice, because of the limits of the current tests, it may be more reasonable to expand this to two consecutive viral load results above 200 copies/ml.
Dr Vella also recognised the importance of individualising approaches depending on the situation of each patient. In someone failing a first therapy, an early switch may minimise developing resistance and maximise the response for the following salvage regimen. Patients with fewer options may require a more conservative approach (waiting for confirmed viral rebound or CD4 decline) especially as the interval from viral escape to clinical failure may vary significantly from person to person.
This highlights that determining the individual reasons for every failure (again echoing Mellors ICAAC address last Autumn) is essential before prescribing a subsequent drug combination. Without results from large second- and third-line therapy trials it remains important to identify predictors of salvage therapy response - especially resistance testing - in understanding reasons for failure and guiding next regimen choice.
Many restrospective studies seem to show an incremental benefit of resistance testing over prescribing based only on treatment history (Deeks, Herrigan and others). Indeed the difference in the Viradapt study was dramatic after only three months. Sustained benefit of the added value of providing resistance testing beyond 12 weeks is still awaited. Both geno- and phenotyping assays provide information only on the predominant variants, ignoring the archived mutants selected during previous treatment which may still be persisting in the patient at lower levels. Drug sensitivity, of course, cannot predict success but it's absence can be predictive of failure.
Examples given for the need to understand how to use current drugs better included the PK and compliance benefits from the dual-protease ritonavir/indinavir combination and a better understanding of the mechanisms of action for hydroxyurea. The first has produced a more tolerable protease combination - BID with no diet restrictions - and has been seen to reduce the risk of side effects in retrospective studies [8,9,10]. Hydroxyurea inhibits ribonucleotide reductase, enhances antiviral activities of dideonucleosides and has no risk of viral resistance. It may also play a role in the preservation of HIV-1 specific LPA responses in circumstances highlighted by the much discussed 'Berlin' patient [11, 12]. Future success will also depend on the activity of new drugs against resistant virus by being from different structural groups, or better tolerability enabling patients to reach very high trough levels above the IC50 of the resistant virus.
Dr Vella finally turned to the role of the immune system as our 'other drug' and the question of how it can best help in the management of HIV-infection. Artificial infusion of HIV specific CTL's is able to reduce HIV viral load either in terms of PBMC or plasma RNA [13]. To quote: 'the results provide direct evidience that HIV specific CTLs target sites of HIV replication and mediate antiviral activity and indicate that the development of immuno-therapeutic approaches to sustain a strong CTL response to HIV may be a useful adjunct to treatment of HIV infection'.
Results from Ho and others, show evidence of sustained anti-HIV response after potent HAART, that in some cases this may help to contain HIV replication after cessation of therapy (see discussion below in this issue of "Doctor Fax"). Vella highlighted the importance of investigating maintenance, potentiation and induction of HIV specific responses and activation of the latently infected reservoirs which are currently limiting all HAART treatment. Eradication estimates currently run at 23 years (of maximally suppressive treatment), but more optimistically, this reservoir remains small (no more than 106 cells) and contains drug sensitive virus. This justifies Robert Siliciano's 'reasons for hope' - to activate or delete this reservoir keeping this goal within reach (although not with the currently available regimens).
In conclusion came the regular wish list for more and better drugs and progress in research on immune-based therapy and eradication. It was tempered with important practical recommendations to probably use more potent regimens and to include drug susceptibility testing and monitoring of drug levels as a standard part of HIV disease management.
References:
1. Vella S: Antiretroviral therapy in adults [State-of-the-Art Lecture L1]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
2. Mocroft A, Vella S, Benfield TL, et al: Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet 352(9142):1725-30, 1998.
3. Palella FJ, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338(13):853-60, 1998.
4. Tashima K, Staszewski S, Stryker R, et al: A phase III, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz + indinavir, versus EFV + zidovudine + lamivudine, versus IDV + ZDV + 3TC at 48 weeks [LB-16]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
5. Van Heeswijk R, Lipniacki A, Nowak P, et al: Initial HIV-1 clearance rate in antiretroviral therapy with D4T plus DDI and either NVP, IDV, or 3TC [Abstract 634]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999
6. Katlama C, Murphy R, Johnson V, et al: The Atlantic Study: a randomised open-label study comparing two protease inhibitors (PI)-sparing antiretroviral strategies versus a standard PI-containing regimen [Abstract 18]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
7. Lewin S, Vesanen M, Kostrikis L, et al: The use of real-time PCR to quantify HIV unspliced (US) mRNA in patients on effective antiretroviral therapy [Abstract 155]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
8. Saah AJ, Winchell G, Seniuk M, et al: Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) ritonavir (RTV) combinations in healthy volunteers [Abstract 362]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
9. Burger DM, Hugen PWH, Prins JM, et al.: Pharmacokinetics of an Indinavir/Ritonavir 800/100mg BID regimen [Abstract 363]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
10. Workman C, Whittaker W, Dyer W, et al. Combining Ritonavir and Indinavir Decreases IDV Associated Nephrolithiasis [Abstract 677]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
11. Lori F, Rosenberg E, Jessen H, et al. Tailoring Drug Treatments with the Use of Hydroxyurea [Abstract 401]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
12. Lisziewicz J, Rosenberg E, Lieberman J, et al: Immune Control of HIV after Suspension of Therapy [Abstract 351]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999
13. Brodie SJ, Lewinsohn DA, Patterson BK, et al: In vivo migration and function of transferred HIV-1-specific cytotoxic T cells. Nature Medicine 5(1):34-41, 1999.
Paul Blanchard, ATP
Fisher and colleagues of Zurich investigated chronically infected patients treated with ZDV/3TC or ZDV/3TC/RTV. HIV-RT PCR was used to quantitate HIV1 RNA in plasma, PBMC's and tonsillar lymphoid tissue. Serial quantitations were made over the 48-94 weeks of follow-up. Despite 10/16 patients reaching less than 20 copies/mL plasma HIV RNA within 3-6 months and remaining <20 copies evidence of cell associated HIV transcription was detected throughout up to 20 months of follow-up. [2] Replication competent virus was also readily identified by Tremblay and colleagues by using selective culture of PBMC's in the presence of IL-2 and a monoclonal antibody to eliminate CD8 cells [3]. Again, patients were judged to be fully suppressed by potent antiretrovirals with 14 months of plasma HIV RNA levels <50 copies/mL.
A complete poster session at this meeting (Poster Session 42) was devoted to evidence for the compartmentalisation of HIV in vivo. Roberts and colleagues of the Centre for Disease Control, Atlanta presented compelling data that such compartmentalisation may even exist within subsets of the peripheral blood mononucleocytes (PBMC) [6]. A technique was developed to detect minority subspecies which involved culturing PBMC's in presence of drug to allow outgrowth of any phenotypically resistant virus present. Drug naive early seroconverters were used as the subjects in this study and different phenotypes of HIV were found to exist in the T-cell and monocyte subsets. Emergence of zidovudine resistant virus from the T-cell but not the monocyte subset was observed in two patient samples.
References:
1. Lewin S, Vesanen M, Kostrikis L, et al: The use of real-time PCR to quantify HIV unspliced (US) mRNA in patients on effective antiretroviral therapy [Abstract 155]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
2. Fischer M, Kallivroussis A, Opravil M, et al: HIV-1 RNA transcription in blood cells of patients with undetectable plasma viral loads [Abstract 154]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
3. Tremblay C, Merrill DP, Wong J, et al: Study of cell-associated HIV-1 using a quantitative CD4 lymphocyte outgrowth assay [Abstract 162]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
4. Derbeyn CA, Kilby JM, Miralles GD, et al: Discrimination between active and inducible viral RNA transcription in HIV-1 infected subjects regardless of effective antiretroviral therapy [Abstract 5]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
5. Wong J, Gunthard H, Fiscus S, et al: Residual HIV RNA and DNA in lymph node and HIV RNA in genital secretions and in CSF after two years of suppression of viremia in the Merck 035 cohort [Abstract 6].
6. Roberts B, Pau C, Weinstock H, et al. Phenotypic Evidence for Cellular Compartmentalization of AZT-resistant HIV-1 [Abstract 299]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
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While suppressing viral load to <50 copies/mL is today's target, it is obviously just an artefact of currently available technology. Using a model of total suppression = no replication = no viral evolution = continued durability - then the goal should self-evidently not be <50, but a VL of zero. The big question is whether this is achievable, or even currently being achieved? As well as the data presented above, previous studies have identified changes in hypervariable regions of the envelope suggesting viral drift. Any possibility that de novo cycles of infection are taking place would suggest that the clock marking the time frame of eradication is continually reset. |
Paul Blanchard, ATP
Several presentations at this conference, however, reported data on a small number of patients in whom the expected rebound on cessation of therapy was not observed. An intriguing late-breaker, one slide presentation and other posters hinted at interesting preliminary observations on this phenomenon. Rationales for continued viral suppression after withdrawal of ARV's were discussed, as well as an exciting extension of these hypotheses into a strategy for pulsed (on-off), intermittent therapy.
A follow-up study of 38 newly infected subjects enrolled in combination therapy trials between July 1995 and February 1997 was presented by Marty Markowitz of the Aaron Diamond AIDS Research Centre. 4/38 patients were identified who discontinued their therapy after more than one year (mean 17.2 months) due to drug intolerability but with good viral suppression (<400 copies/mL plasma HIV-RNA by 7.1 weeks sustained over the period of treatment). 2/4 of these subjects HIV-RNA rebounded back to and beyond baseline after treatment was stopped. The remaining 2 subjects, however, maintained plasma viral load <400 copies for 14 and 21 months (their most recent RNA levels were 174 and 50 copies/mL respectively) [1].
A second presentation in a similar group of subjects assessed HIV-specific cytotoxic T lymphocyte (CTL) response in 4/12 subjects treated within 90 days of becoming HIV-infected with a combination of ZDV/3TC/RTV [2]. Virologic response to treatment was good, with HIV RNA levels falling below 500 copies/mL within 2 weeks of initiation of therapy. 2/4 subjects ended therapy abruptly, and of these, one maintained a low viral load without ARV's for 4 months, the second had a rapid viral rebound. The other 2 patients experienced poor adherence, discontinued therapy with a rebound in plasma viraemia, resumed therapy for variable periods then finally ceased altogether. In both, HIV-RNA has remained <500 copies/mL for 17 and 24 months while off antiretrovirals.
A broad and strong HIV-specific CTL response (env, gag, pol and nef) was sustained though out antiretroviral therapy in these four subjects. In the 2 subjects who ended therapy abruptly, waning of CTL response was temporally associated with reappearance of plasma viraemia. The intermittently adherent subjects, however, have continued to maintain broad and strong CTL responses in association with their continued viral suppression. Interestingly, CTL response was boosted during periods of poor adherence when low levels of viral replication took place leading to the suggestion that intermittent drug discontinuation may play a role in the boosting of HIV-specific CTL responses. These CTL responses may additionally contribute to prolonged suppression of viral replication once drug therapy is stopped.
Both of the studies reported above were in patients with recent HIV-infection. The only presentation to discuss discontinuation of therapy in chronically infected patients was presented by F. Garcia on behalf of the Spanish EARTH-1 study team [3]. This study was of d4T/3TC/RTV in early disease (CD4 >500 cells/mm3 and VL >10,000 copies). Eight of nine patients at one study centre who had experienced plasma VL below 20 copies/mL (5/8 were below 5 copies/mL) at one year decided to discontinue their antiretroviral medication. HIV RNA viral load was also measured in CSF and tonsillar tissue just prior to cessation of therapy and was found to be below 20 copies/mL in all cases in CSF and below 40 copies/mg tissue in all 5 patients who had tonsils present. In all patients plasma viral load was found to rebound with a mean doubling time of 2.1 ((0.89) days. Three of the eight patients (all of whom were below 5 copies/mL on treatment) achieved a peak viral load rebound more than 0.5 log higher than their pre-treatment values. During viral rebound CD4+ lymphocyte percentage dropped non-significantly from a mean of 45% to 36% (p=0.07) and activated CD8+ (CD38+) lymphocytes increased from a mean of 56% to 66% (p=0.05). The same combination of antiretrovirals were reinitiated in all eight patients after 28 days and plasma viral load dropped to below 20 copies/mL in all subjects within one month. The pattern of viral rebound in these patients was similar to that reported in the paper by Jubault et al. [4].
Possibly the most celebrated case of maintained viral suppression after treatment discontinuation is the so-called "Berlin" patient. This 29-year-old man was initially treated with a combination of ddI, hydroxyurea and indinavir approximately 57 days after exposure to HIV, and prior to complete seroconversion. Baseline viral load one week prior and just before initiation of therapy was 80,041 and 89,390 copies/mL respectively. HIV RNA fell rapidly and reached <500 copies/mL after 12 days of treatment. All antiretrovirals were suspended during an episode of epididymitis at day 15 for 7 days and HIV RNA was seen to rebound to 5,356 copies/mL. The same antiretroviral combination was then restarted and viral load again fell to <500 copies/mL after a further 30 days. A second treatment interruption of 16 days occurred at this point due to an episode of acute hepatitis A. Despite concurrent viral hepatitis and no antiretroviral therapy, during this second suspension of treatment plasma VL remained below 500 copies/mL. HIV treatment with ddI, hydroxyurea and indinavir was then recommenced but with intermittent adherence for a further 5 weeks. Finally, 156 days following the original introduction of therapy, this patient decided to permanently stop his antiretroviral treatment.
At the time of this report, five hundred and fifty one days after this final treatment discontinuation, plasma HIV RNA levels remain below 500 copies/mL. A poster presentation [5] reported continued low levels of HIV RNA in the lymph nodes of this patient and replication competent virus in resting CD4+ lymphocytes. Additionally, elevated levels of CD8+CD28+ T lymphocytes suggest an ongoing cell mediated response to low level residual HIV replication. Lack of plasma HIV RNA rebound is not, therefore, deemed to be due to eradication of replication competent HIV, but rather due to host control. Absence of neutralising antibodies also suggests this control is not being mediated by a humoral immune response. As with the patients discussed earlier, the presence of strong anti-HIV specific (p-24) T-helper responses and CTL responses were found to be associated with lack of HIV RNA rebound.
In the late-breaker session Dr Franco Lori of the Research Institute for Genetic and Human Therapy (RIGHT) speculated on the mechanisms of viral suppression seen in the "Berlin" patient [6]. Was it the early initiation of treatment, the inclusion of hydroxyurea in the antiretroviral combination, or the intermittent nature of therapy which were important in the lack of viral rebound?
Lori then went on to describe preliminary results from two on-going prospective studies designed to assess the contribution of intermittent antiretroviral administration to host control of HIV. The first of these studies is being carried out in three SIV-infected macaques receiving treatment with ddI, hydroxyurea and PMPA (HIV protease inhibitors are not active against SIV). Treatment was initiated 28 days post-exposure when the animals had a mean baseline viraemia of 5.8log10 copies/mL. An intermittent treatment schedule of two cycles of 3 weeks therapy followed by treatment interruption was used. Although viral rebound occurred on cessation of therapy it reached a steady state of less than 5,000 copies/mL for 6 weeks during the first interruption and has remained below 200 copies/mL out to 100 days during the current second interruption.
In parallel to this study a similar protocol was initiated in three human patients All three were complete seroconverters with stable viraemia (719,000, 22,665 and 33,707 copies/mL plasma HIV RNA). Treatment was initiated within one year of primary infection using a combination of ddI, hydroxyurea and either a protease inhibitor or d4T. Three weeks of therapy were followed by one week of interruption allowing viral load to rebound to around 5,000 copies/mL. A further 3 months of therapy were then initiated before a second interruption, again allowing viral load to rebound to about 5,000 copies/mL. Another 3-month cycle of therapy was again initiated when this level of rebound had been reached. At each treatment interruption the time taken for viral load to rebound to 5,000 copies was extended. After the initial 3 weeks of therapy 5,000 copies was reached in one week in all 3 subjects. During the second treatment interruption this was extended to 14 days (range 11-19), and then to 37 days (range 27-48) during the third interruption. These cycles of on-off therapy are still ongoing.
Lori concluded that both the animal and human studies suggest that serial treatment interruptions may prolong the time to viral rebound and induce host control of viral replication in the absence of therapy. Periods of treatment cessation without significant plasma viraemia may be prolonged. Further randomised trials would be needed to establish the relative importance of inclusion of hydroxyurea, treatment "early" in infection or the intermittent interruptions in treatment in these observed phenomena.
References:
1. Markowitz M, Tenner-Racz K, Zhang L, et al: The long-term responses to combination therapy commenced early in HIV infection: 3-year follow-up. What's happened since Vancouver? [Abstract 636]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
2. Ortiz GM, Jin X, Demoitie MA, et al: Containment of breakthrough HIV plasma viremia in the absence of antiretroviral drug therapy is associated with a broad and vigorous HIV-specific cytotoxic T lymphocyte response [Abstract 256]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
3. Garcia F, Plana M, Vidal C, et al: Quick viral load rebound after one year of successful HAART in chronic HIV-1 infected patients in very early stages [Abstract 629]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999
4. Jubault V, Burgard M, Le Corfec E, et al: High rebound of plasma and cellular HIV load after discontinuation of triple therapy. AIDS 12(17): 2359-2359, 1998.
5. Lisziewicz J, Rosenberg E, Lieberman J, et al: Immune Control of HIV after Suspension of Therapy [Abstract 351]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999
6. Lori F, Zinn D, Varga G, et al: Intermittent drug therapy increases the time to HIV rebound in humans and induces the control of SIV after treatment interruption in monkeys [Abstract LB6]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, Ill, 1999.
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Eradication of infection appears increasingly unlikely with current therapeutic approaches and major uncertainties exist over maintaining full suppression over the long-term (25-30 yrs? Can a body survive that length of time on nucleoside DNA chain terminators and hyperlipidaemia inducing PI's?). Hence, additional strategies where difficult drug therapies may be suspended for periods of time would be extremely welcome. The rationale behind intermittent therapy is that controlled "spikes" of viraemia may act as an autologous vaccination stimulating the type of HIV-specific T-helper and CTL response seen in primary infection and persisting in long term non-progressors. Total viral suppression by antiretrovirals during chronic HIV-disease may be preventing the levels of HIV antigens needed to produce and maintain these host immune responses thought to be valuable in the immune containment of HIV replication. An alternative strategy for providing HIV antigen during antiretroviral therapy is that of therapeutic vaccination - the current lead candidate of which is Remune. This gp-120 depleted preparation of HIV may help rebuild anti-HIV CTL responses without the risk of immune dammage that comes with periods of live viral replication. Further data on Remune was also presented at Chicago and will be reported in a future issue of ATP's "Doctor Fax". Low level viral replication during antiretroviral therapy may be equally useful in enabling a low grade viraemia to stimulate these responses. However, viral escape of drug resistant mutants and uncontainable viraemia with the potential to cause further disease is a very real possibility when replication is ongoing in the face a drug pressure. It should be emphasised that these exciting results are early and preliminary. It should also be noted that there are a number of extremely important concerns which should also be factored into the consideration of intermittent therapy. Firstly it should be made very clear that intermittent therapy is NOT the same as poor adherence. ALL drugs are started and stopped with clearly predetermined criteria (ie. for a set number of days or allowing VL to rise to a decided level). There is also a real concern that resistance may become a greater risk during continued cycles of intermittent therapy. Antiretrovirals with long half-lives may take up to a week for their levels to "decay". During this time there may be extended periods where drug levels are producing the ideal conditions for resistant virus to arise. Drug levels will fall at varying rates dependent on the PK of individual agents in a given combination leaving the longest acting component as monotherapy until all drug is eliminated.-(although see DocFax 62 - "Intermittent selection pressure with zidovudine plus zalcitabine treatment reduces the emergence in vivo of zidovudine resistance HIV mutations".) Of note, the 3 patients in Lori's intermittent administration study were full seroconverters. Although it is unlikely that they had major immune dysfunction they were, none the less, chronically infected. |
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ISSUES 64 & 65 OF ATP's DOCTOR FAX WILL CONTINUE COVERAGE OF THE RETROVIRUS CONFERENCE LOOKING AT ANTIRETROVIRAL TRIALS, IMMUNOLOGY, PATHOGENESIS AND OPPORTUNISTIC EVENTS IN AIDS.
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