1 The FASEB Journal Research Communication Short cycles of antiretroviral drugs provide intermittent yet effective therapy: a pilot study in 48 patients with chronic HIV infection Jacques Leibowitch,*,,1 Dominique Mathez,* Pierre de Truchis, Christian Perronne,, and Jean-Claude Melchior,, *Immunology and Virology Unit, Clinical Infectious Disease Unit, and Clinical Nutrition and Infectious Disease Unit, Department of Internal Medicine and Infectious Diseases, Raymond Poincaré Hospital, Assistance Publique Hôpitaux de Paris, Garches, France; and University and Medical School, Paris-Île-de-France-Ouest, Saint Quentin en Yvelines, Versailles, France ABSTRACT The present study evaluated the efficacy of intermittent antiviral treatment administered to HIVinfected patients under stepwise reductions in weekly medication. Forty-eight patients were invited to reduce their antiviral medication to 5 consecutive days per week; after control over HIV activity was ascertained, antiviral drugs were cut to 4 consecutive days per week. Of the 48, 39 then reduced medicines further to 3 d, and 12 of those eventually undertook a 2 d/wk schedule. Clinical and immunological status and plasma HIV load were repeatedly monitored. HIV was unremittingly maintained below detection levels in all patients under either 5- or 4-d/wk treatment regimens, for a mean wk/patient (5-d regimen) and wk/ patient (4-d regimen). Of the 39 patients under 3-d regimens, 35 maintained optimal control over HIV activity for a mean wk, as did 10 of the 12 under 2-d regimens, for wk. Summing up treatment < 5 d/wk, plasma HIV remained below detection levels for a cumulative 8895 wk (170 patientyr). No major HIV-related clinical event was reported. and CD4 T-cell counts and percentages readily increased over the last value noted under the 7-d treatment course. Viral failure was documented in 6 of the 48 patients: 4 under a 3-d/wk regimen, 2 under a 2-d/wk regimen. All 6 patients had their treatment swiftly set back to a 7-d/wk regimen, resulting in rapid control over HIV replication. In summary, intermittent antiretroviral regimens optimally suppressed HIV in patients taking antiviral medicines 5 and 4 d/wk, as well as in a substantial proportion of patients under 3- or 2-d/wk antiviral regimens, reducing both expenses and, possibly, drug toxicity. Controlled prospective clinical trials are warranted before considering short weekly cycles of antiretroviral medicines an alternative in the management of chronically HIV-infected patients. Leibowitch, J., Mathez, D., de Truchis, P., Perronne, C., Melchior, J. C. Short cycles of antiretroviral drugs provide intermittent yet effective therapy: a pilot study in 48 patients with chronic HIV infection. FASEB J. 24, (2010). Key Words: intermittent HIV treatment HIV genotype cost of treatment observance antiviral regimen Despite progress in anti-hiv drug combinations, none have reached the aim of a definitive cure (1). Uninterrupted antiretroviral therapy is required for the unfailing control of HIV replication in the patient, as shown by any durable treatment interruption that entails a resumption of full blown HIV activity (2), which could also lead to increased morbidity, as has been reported (3). Yet, stringent observance to anti- HIV treatment may bring pill-fatigued patients to omit their medicines, while endless chemotherapy of that nature may be fraught with cumulative collateral damage (4) (5). Although the newer anti-hiv combinations may have lower intrinsic toxicities (6), many of the current anti-hiv drug cocktails are known to alter lipid and glucose metabolism (7). Epidemiological data have raised concern about heart disease, diabetes, liver disease, or certain forms of cancer with highly active antiretroviral therapy (HAART) in aging HIV-infected patients over the long term (8 11). In addition, the cost of HIV treatment remains heavy for the world community at large, and may discourage treatment altogether in many developing countries. Consequently, the search for more time-limited anti-hiv interventions not resulting in the resumption of HIV viremia has become a highly desirable yet unattained goal. In that context, since 2003, 48 patients under our longtime care accepted a stepwise reduction over months of time in their weekly antiviral drug regimens, from a regular 7 d/wk to 5, 4, 3 and in some patients, 2 d/wk. 1 Correspondence: Immunology and Virology Unit, Hôpital Raymond Poincaré, 104 Bd. Raymond Poincaré, Garches, France. doi: /fj /10/ FASEB 1649
2 MATERIALS AND METHODS Patients and treatment schedule Forty-eight HIV-infected patients were selected on the basis of both their volunteering to follow an uncharted course of anti-hiv treatment, and their adherence to repeated monitoring. This was done in our clinic with the approval of the Raymond Poincaré Hospital Ethics Review Committee on Infectious Diseases. An individualized letter acknowledging the off-label, nonvalidated status of these exploratory prescriptions at their onset was personally addressed to and signed by each individual patient. It was in essence proposed that patients reduce their treatment to 5 consecutive days per week; after suppression of HIV activity was ascertained, patients were invited to reduce treatment to 4 consecutive days per week. Treatment was eventually reduced to 3 d/wk, and finally, in a smaller set of patients, to 2 d/wk. The triple or quadruple antiretroviral combinations prescribed may have varied over time in the individual participant, at the participant s convenience, or in relation to unwanted effects or to the availability of newer inviting drug regimens. Monitoring HIV viremia, blood T-lymphocyte counts HIV replication was monitored by a mean of 4 virological plasma samplings/yr. For patients receiving a 3- or 2-d/wk regimen, plasma samplings were drawn every 2 3 wk. Plasma HIV levels were measured by a commercial assay, the Amplicor HIV-1 Monitor test (Roche Diagnostics GmbH, Mannheim, Germany) followed from 2007 onwards by the Cobas AmpliPrep/Cobas Taqman HIV-1 test (Roche Diagnostics). Plasma HIV spiking over 50 copies/ml at 2 consecutive dosages within 1 mo established viral escape, leading to antiviral treatment modifications. Short of that criterion, an isolated plasma HIV spike one not confirmed as actual HIV viremia in a subsequent specimen obtained within 1 mo was considered a nonmeaningful HIV blip. T-lymphocyte counts and subsets were assayed before treatment and at various times after therapy was initiated from fresh EDTA blood, using an automated cytofluorometric assay system (Beckman Coulter, Fullerton, CA, USA). Absolute white cell counts and relative percentages to whole lymphocyte counts were determined with an automated Beckman Coulter counter. HIV-1 genotyping was performed using the Trugene HIV-1 Genotyping Kit (Siemens, Munich, Germany), according to the manufacturer s specifications. Each sampled virus had been derived from a frozen archival plasma specimen obtained from the patient 3 mo prior to the initiation of the regular 7-d/wk treatment regimen. Antecedent patient treatment history and previous HIV-1 genotypes related to past treatment failures were collated as available. Antecedent treatment history and HIV genotypes antecedent to intermittent treatment Four patients had never taken anti-hiv treatment before an antiviral combination was given 7 d/wk. The other 44 patients had been treated at one to several instances, and 14 of them had a history of one to several virological failures under various 7-d/wk antiviral regimens (mono-, bi-, or tridrug therapies). In 11 of those 14 patients, the dominant HIV strain did show resistance mutations (from 1 to 6 mutations) within the reverse-transcriptase genome. Before entering the 7-d/wk treatment regimen, 10 of the 14 patients who had endured viral treatment failures eventually presented with a wild-type HIV genotype, following past momentary treatment interruptions of 3 mo each. Preintermittent treatment genotypes were available for 47 of the 48 patients: 44 patients presented with a dominant wild-type HIV species; 3 showed a dominant HIV species bearing one to several mutations on the reverse transcriptase: a single 184 I mutation in 1 patient, and 5 mutations in the other 2 patients (67N 69S 70R 184V 103N and 74V 115F 184V 100I 103N, respectively). In the latter 3 patients, care was taken to select the drug combinations that would most likely supersede the mutated viruses. HIV genotype could not be assayed in 1 patient with a viral load below detection level at the onset of the 7-d/wk treatment phase. Statistical analysis Results are presented as means sd. Wilcoxon signed-rank test was used to test the paired differences in values obtained from baseline to each step of study for significance. A 2 test adapted for small numbers was used to test the difference in blip rates between the different groups. RESULTS Patient characteristics Patient characteristics are summarized in Table 1. Most of the patients had been treated, some heavily, before TABLE 1. Baseline characteristics of the 48 patients Characteristic Value Sex Female 11 Male 37 Age (35 79) Nadir blood TCD4 cells (16 313) Nadir blood TCD4 (%) 11 6 (1 27) VL max log ( ) Total follow up prior to study (yr) ( ) Antecedent AIDS events and/or CD4 200 l n (%) 38 (79.2%) Antiretroviral treatment prior to study n (%) 44 (91.7%) Duration of antecedent treatment (yr) ( ) Prior treatment interruptions (n) 1 to 5 (median 2) Values in parentheses indicate range unless stated otherwise Vol. 24 June 2010 The FASEB Journal LEIBOWITCH ET AL.
3 entering the study. The majority had had one or several clinically AIDS defining events and/or CD4 cell counts 200/ml. Decremented weekly medicine intake flow chart All 48 patients were treated with antiviral combinations taken daily, 7 d/wk, for wk (range wk). Subsequently, in each patient, HIV viremia had to stand below detection levels before reduction in the weekly antiviral schedule was considered. Forty-seven patients first reduced their weekly medicine intake to 5 consecutive days on, 2 d off, during wk ( wk). Forty-eight patients reduced antiviral intake to 4 consecutive days, with 3 d off, for wk ( wk). Thirty-nine of the 48 patients proceeded to the 3-d/wk, schedule, remaining off antivirals for the next 4 d for wk (6 to 143 wk). Twelve of the 39 patients further reduced antiviral intake to 2 d of treatment, either consecutive (8 patients), or days apart (Monday and Thursday, 4 patients), remaining off treatment the other 5 d of the week. The 12 stayed on those 2-d schedules for wk (12 51 wk). Antiviral combinations Emtricitabine (FTC) tenofovir disoproxil fumarate (TDF) was the preferred backbone nucleoside/nucleotide reversetranscriptase inhibitor (NRTI) pair, totaling 91.1% of all our prescriptions; 32.4% were combined with Efavirenz (EFV), 35.6% to a ritonavir-boosted (r) HIV protease inhibitor (PI): atazanavir (ATZ), lopinavir (LPV), darunavir (DRV), or fosamprenavir (fapv), ranked as the preferred prescription order of all prescriptions. Didanosine (DDI) was combined with FTC TDF to constitute a triplet NRTI backbone prescribed in 20.4% of all prescriptions in combination with one of the following nonnucleoside reverse-transcriptase inhibitors (NNRTIs): nevirapine (NVP), efavirenz (EFV), or etravirine (ETV). Raltegravir (RAL) and other antiviral drugs, rarely prescribed, are posted in Table 2. On the whole, NNRTI or boosted PI-based combinations represented 56.5 and 40.4% of all prescriptions, respectively. Twelve of the 48 patients remained with the same combination of drugs (triple or quadruple) throughout the period of observation. The other 36 took 2 different antiviral combinations for a mean wk. Exemplary illustrations of various treatment schemes and their eventual alteration throughout follow-up under treatment are presented in Fig. 1. Clinical and immunological outcomes Over the cumulated 8928 wk of follow-up under intermittent treatment, not one major HIV-related clinical event was reported (Table 3). Two episodes of selflimited and circumscribed herpes zoster emerged in 2 patients. Of the 5 men with antecedent HIV-related cutaneous Kaposi s sarcoma, none suffered recurrence. One patient had to be treated for an invasive prostate cancer, and one, at 76 yr of age and with a personal and family history of vascular disease, suffered a limited myocardial infarct, 5 yr into intermittent antiviral treatment. These two events were not considered as causally related either to HIV infection or to antiretroviral treatment. Mean blood TCD4 lymphocytes (absolute counts and percentages) increased from d 0 to the end of the 7-d/wk treatment period (P 0.02). From then on, mean CD4 counts and percentages in each of the decremented treatment strata rose substantially over the levels noted in the last dosage made under the 7-d/wk treatment schedule. Virological results On the whole, the 48 patients cumulated a total of 8895 wk under intermittent treatment, 5 d/wk, maintaining HIV at undetectable levels for a mean of wk (range wk). As stated above, HIV viremia had to be under full suppression before the weekly antiviral medication intakes were eventually cut down. Unremitting control over HIV activity was accordingly ascertained in 47 patients who remained under effective treatment 5 d/wk for wk ( wk), 48 patients under effective treatment 4 d/wk for wk (14 217), 35 of 39 patients treated effectively 3 d/wk for wk (6 143), and 10 of 12 patients successfully treated 2 d/wk for wk (12 51 TABLE 2. Treatment combinations used NRTI NNRTI PI II IP NNRTI II NNRTI Total FTC/3TC TDF DDI FTC/3TC TDF ABC TDF ABC FTC TDF ABC 3TC DDI TDF None Total Data are expressed as percentages of all treatment weeks. II, integrase inhibitor; 3TC, lamivudine; ABC, abacavir. See Results, Antiviral Combinations, for other abbreviations. EFFECTIVE SHORT CYCLES OF ANTIRETROVIRAL DRUGS 1651
4 Figure 1. Four representative treatment schemes in 4 individual patients. A) Patient 5 was treated with a combination of 4 HIV-1 reverse-transcrptase inhibitors: 2 nucleoside analogues (DDI and FTC), plus a pseudonucleotide analogue (TDF), and a non-nucleoside HIV-1 reverse-transcriptase inhibitor (NVP). B) Patient 19, of Ivory Coast ancestry, was successively treated with a quadruple combination of HIV-1 reverse-transcriptase inhibitors, lamivudine (3TC) TDF EFV DDI; then a triple combination of FTC (replacing 3TC) TDF EFV, which was eventually complemented with DDI when EFV was reduced to 1/3 of the recommended daily dosage (patient 129 carries a cytochrome p450 homozygous allele 2B6, known to prolong EFV half-life). C) Patient 49 was maintained with combinations of a pair of reverse-transcriptase inhibitors, first 3TC and then its equivalent FTC, nucleosides combined with TDF, a nucleotide analogue, in association with 2 HIV-1 PIs, first ATZ and then LPV, the latter at half the recommended daily dosage. Both PIs were boosted with ritonavir (Rv). D) Patient 4 was successively treated with a quadruple combination of HIV-1 reverse-transcriptase FTC TDF EFV DDI; then a similar triple combination omitting DDI, with EFV at 2/3 the recommended daily dosage; EFV was later omitted in favor of an HIV-1 PI, LPV, which was abandoned in favor of ATZ, another HIV-1 PI. Both of the latter drugs were boosted with Rv. wk). Altogether, of the 48 patients under intermittent treatment 4 d/wk, HIV replication remained under unabated control in 42. Six of the 48 patients had a documented viral failure, as defined by 2 consecutive plasma HIV levels 50 copies/ml: 4 were on a 3-d/wk, 2 on a 2-d/wk antiviral schedule. In 5 of the 6 whose HIV escaped control, plasma HIV spiked at 1000 copies/ml, and 4 patients experienced 200 copies/ml for a duration of 2 mo before adjusted treatment regained control over HIV TABLE 3. Virological and immunological outcomes Treatment regimen Patients (n) Cumulated effective treatment (wk) Blips % (viral load determinations) Failures CD4, last specimen of each step CD4/ l % Day0of observational period (55 599) (4 26) 7 d/wk (180) ( ) (6 40) 5 d/wk (222) ( ) (6 43) 4 d/wk (340) ( ) (13 46) 3 d/wk (209) ( ) (12 49) 2 d/wk (87) 2 Insufficient data Data are expressed as means sd, and values in parentheses indicate range, unless stated otherwise Vol. 24 June 2010 The FASEB Journal LEIBOWITCH ET AL.
5 activity. HIV viremia topped at 2300 copies/ml for 2 mo in 1 patient. Table 4 summarizes the duration of time and the composition of the antiretroviral combination during and under which the 6 patients failed. Four patients failed under the 3-d/wk regimen, 1 under EFV 600 mg FTC TDF, a combination that had previously shown optimal control over HIV replication in that same patient under 7-, 4- and 3-d/wk treatment regimens, the latter regimen having been fully effective for 69 wk. Three patients had their viral counts under control with a 4- or 3-d/wk treatment regimen combining a boosted PI with FTC TDF, but then HIV escaped when RAL was introduced into the 3-d/wk treatment in replacement of the boosted-pi regimen. Two patients registered virological failure under a 2- or 3-d/wk regimen of EFV combined with TDF FTC. One patient registered failure under a 2-d/wk regimen of low daily doses of LPVr (400 and then 600 mg, 1 /d). Three patients registered failure under a 3-d/wk regimen with RAL, in combination with FTC TDF in 2 patients and with ABC TDF in 1 patient. Five patients without confirmed viral failure exited the study when their weekly treatment regimens were set back to 7 d/wk: 1 in relation to a false-positive virological result, 3 for personal convenience, and 1 for momentary treatment interruption. The incidence of HIV blips under treatment (Fig. 2) was low, and did not differ under the decreasing 5-, 4-, 3-d/wk treatment regimens compared to the 7-d treatment phase; HIV blips rose significantly to a 12.8% incidence under the 2-d/wk regimen (P 0.012). Patient follow-up and HIV genotypes under intermittent treatment In 5 of the 6 patients whose virus escaped under intermittent treatment, one single new mutation emerged within the HIV reverse transcriptase as a 184I amino acid change in 3 patients, and a 103N amino acid change in 1 other patient. The fifth patient had had an additional 65R mutation in his previously highly mutated virus (carrying amino acid changes at positions 74V, 115F, 184V, 100I, and 103N in the RT genome). No mutation on the HIV integrase emerged in any of the 3 patients who failed under a RAL-based regimen. No genotype was available for the sixth failing TABLE 4. Duration of controlled HIV viremia prior to virological failure in 6 patients Duration prior to failure (wk) ARV combinations used during relevant period Drug regimen 12 FTC, TDF, LPVr 2d/wk 19 FTC, TDF, EFV 2d/wk 6 FTC, TDF, RAL 3d/wk 16 ABC, TDF, RAL 3d/wk 33 FTC, TDF, RAL 3d/wk 72 FTC, TDF, EFV 3d/wk Figure 2. Virological efficacy of reduced treatment regimens. patient, because his viral load under escape remained 200 copies/ml. The 6 patients with virological failure were reassigned to a 7-d/wk regimen, with a new combination, and all of them had their HIV levels under control within 2 mo, remaining so for the past 26 to 65 wk, with 5 of 6 already back to 5-d/wk treatment regimens. DISCUSSION In our hands, short cycles of intermittent antiviral treatment seemed safe and effective: under the 5 d on/2 d off treatment regimens, plasma HIV viremia was fully suppressed for a mean 56 wk, totaling 2626 cumulative weeks of unrelentingly effective therapy in 47 patients; similarly, in 48 patients under the 4 d on/3 d off regimens, HIV remained under optimal control for a mean 84 wk, and 4022 cumulative weeks of unremittingly efficient treatment. Antiviral treatment taken only 3 d/wk fully suppressed plasma viremia for a mean 48 wk, and a total of 1958 cumulative weeks under such abridged treatment. In the 12 patients who cut their medication down to 2 d/wk, HIV remained fully controlled for a mean 24 wk, representing 289 cumulated weeks of effective treatment under the sharpest treatment abridgment. History of antiviral treatment failures was not uncommon in our patients, which led to the emergence of mutated resistant HIVs. However, a previously failed treatment could not be implicated in viral failure except for 1 of the 6 registered failures. In fact, most pretreatment HIV strains were of the wild type. When HIV had been resistant or when patients had a recorded past treatment failure HIV had been left to replicate for months, and freely so, without the selective pressure of antiviral drugs, before intermittent treatment was initiated. Whatever mutated virus would have been archived previously in those patients, they would EFFECTIVE SHORT CYCLES OF ANTIRETROVIRAL DRUGS 1653
6 have been diluted out during the drug-free HIV recycling periods, to the point where previously mutated dominant HIV species were apparently outgrown, as became apparent on a subsequent genotype. Three causes of failure could be identified after analysis. One was poor adherence to treatment; in one patient, failing at a time when his private life went into unanticipated turmoil, and HIV escaped under a combination and weekly regimen that had fully suppressed HIV for over a year. A second cause of failure was associated with the reduced daily doses of one component of the antiviral combination because of side effects; 2 patients failed under a 2-d/wk treatment regimen of reduced daily doses of PI or EFV. Finally, a lesser than appropriate antiviral dosage was likely responsible for failure under treatment 3 d/wk in the 3 patients whose treatment was switched to a RAL-based regimen, taken as 400 mg 1 /d only, instead of the recommended daily 400 mg 2 d. That and the scarcity of our data cannot properly substantiate the dismissal of the 3-d/wk treatment strategy. The first study in favor of short-cycle intermittent anti-hiv treatment was published in 2001 by Dybul et al. (12). Ten patients with plasma HIV counts 50 copies/ml entered repeated 7 d on/7 d off HAART cycles with a combination of stavudine lamivudine Indinavir. Patients maintained HIV suppression for 32 to 68 wk. The same group affirmed the concept in a subsequent study (13) in which 8 patients, previously under effective therapy, went onto a series of 7 d on/7 d off HAART cycles with a 1 /d regimen of ddi, 3TC, and EFV. Seven patients maintained suppression of HIV viremia for wk, and 1 withdrew at wk 24. Another study (14) reported on the efficacy of intermittent antiretroviral therapy under a5don/2doff strategy; of 29 patients evaluated at 24 wk, 26 had maintained virological suppression under various triple-antiviral combinations. Three patients failed (11%); 2 failed under a pair of NRTI combinations, one combined with NVP and the other with a boosted PI, and 1 patient failed under a combination of 2 PIs. No other patients failed between 24 and 48 wk of that study. While the 3 above reports tended to support shortcycle intermittent antiretroviral therapy, 2 others have claimed the opposite. Ananworanich et al. (15) compared 3 treatment regimens: uninterrupted vs. CD4 cell-guided treatment interruptions vs. treatment 7 d on/7 d off; of the 36 patients included, 19 (53%) had HIV control failure within the first 12 wk under the 7-d/wk treatment regimen. Cardielo et al. (16) described 26 patients treated 7 d on/7 d off, 8 (31%) of whom had HIV control failure. The limits of short-cycle antiviral therapy so made apparent might be interpreted in the light of the studies by Fisher et al. (17, 18) reporting when HIV would return to detection levels as early as 8 d in 11 of 14 patients in whom treatment had just been interrupted. Of interest, in the latter study, the actual time of HIV resurgence following treatment interruption occurred within a time interval (4 to 14 d) that would span our intermittent treatment schedules. It could be then that subliminally effective antiviral combinations given under short intermittent periods would fail under the 7-d interval, too long indeed for the unrelenting control of HIV replication. Anti-HIV combinations endowed with intrinsic subliminal antiviral effect are expected to demand a level of treatment adherence close to 95%, and certainly no less than 7 d/wk daily medicine intakes to attain and maintain the universally recommended antiviral objectives (19 21). As an example of such a constraint, under a unboosted PI base, viral failures were 2.5 times more frequent when adherence levels were 90%, compared to an optimal antiviral arm resorting to a boosted PI combination (22). On the contrary, less than perfect adherence has been shown to be forgivable if the drug combination is potent enough against the virus (23). The overall antiviral pressure over HIV replication would be expected to diminish when anti-hiv treatment was curtailed, down to the 2-d/wk schedule. As a matter of fact, the frequency of HIV blips rose to 12.5%, significantly higher than the average 2.5% noted indiscriminately at the 7-, 5-, 4-, or 3-d/wk treatment schedule. The incidence of viral blips could depend on the intrinsic anti-hiv effect of a given treatment combination and/or its weekly intake. HIV blip incidence was 2.8% for the preferred NRTI pair (TDF FTC) combined with the PIs DRVr, ATVr, or fapvr; it went to 3.4% (with 2 virological failures) with EFV FTC TDF, rose to 7.7% with LPVr at reduced daily doses, and up to 25% when taken 2 d/wk alone (with 1 recorded failure). The same NRTI pair combined with RAL registered a blip incidence of 19% (with 3 virological failures under a 3-d/wk treatment regimen. In contrast, a null incidence of HIV blips (and no viral failure) was recorded under the quadruple combination of NVP DDI FTC TDF. These considerations may bear relevance when the choices of combinations become an issue in future clinical trials evaluating the intermittent treatment strategy. Clearly, antiviral combinations with suboptimal or limited effect on HIV replication should not be chosen for intermittent short cycled treatment. CONCLUSIONS The data collected in the present study offer a basis for a possible new approach over the unending control of HIV activity by antiviral drugs. The remittent antiviral regimens used here selected among a series of validated powerful antiviral combinations affected HIV activity enough to maintain unremitting control for a cumulative total of 8906 wk under antiviral medicines taken 5 d/wk. It was also suppressive enough to enable patients taking drugs 4 d/wk to maintain faultless control over their HIV for 48 wk (46 patients), 96 wk (38 patients), 144 wk (22 patients), and 192 wk ( Vol. 24 June 2010 The FASEB Journal LEIBOWITCH ET AL.
7 patients). This approach led to an increase in absolute and relative CD4 lymphocyte counts and clinical wellness. Altogether, and to the best of our knowledge, such a set of data has had no match to date in the medical literature. Short repeated cycles of intermittent yet effective antiviral treatment would appear to be a credible alternative strategy to current maximal exposures of patients to antiviral drugs. Intermittent therapy could turn out to be relevant for reducing the burden, cost, and toxicity of unflaggingly effective control over HIV in the treated patient, particularly so in countries with limited resources. The unabated virological control seen here under the selected antiviral regimens stands out as a first. The analytical data presented here could serve as a grounding start for a multicenter prospective and controlled clinical trial endowed with the proper statistical dimensions to establish or refute the noninferiority of the 4- and/or 3- vs. 7-d/wk regimen, re-sorting a larger though still selective set of antiviral combinations in patients more representative of the overall HIV-positive treated population. In our study, 26,569 d of antiviral treatment will have been spared, saving a total of some 800,000 of public funds, and that for only 48 patients, treated for a mean of only 3.5 yr, without HIV returning to ultrasensitive detection levels. REFERENCES 1. Marsden, M. D., and Zack, J. A. (2009) Eradication of HIV: current challenges and new directions. J. Antimicrob. Chemother. 63, Paterson, D. L., Swindells, S., Mohr, J., Brester, M., Vergis, E. N., Squier, C., Wagener, M. M., and Singh N. (2000) Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann. Intern. Med. 133, Ananworanich, J., Phanuphak, N., Nuesch, R., Apateerapong, W., Rojnuckarin, P., Ubolyam, S., Phanuphak, P., and Ruxrungtham K. (2003) Recurring thrombocytopenia associated with structured treatment interruption in patients with human immunodeficiency virus infection. Clin. Infect. Dis. 37, Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr, W. M., Lundgren, J. D., Neaton, J. D., Gordin, F., Abrams, D., Arduino, R. C., Babiker, A., Burman, W., Clumeck, N., Cohen, C. J., Cohn, D., Cooper, D., Darbyshire, J., Emery, S., Fätkenheuer, G., Gazzard, B., Grund, B., Hoy, J., Klingman, K., Losso, M., Markowitz, N., Neuhaus, J., Phillips, A., and Rappoport C. (2006) CD4 count-guided interruption of antiretroviral treatment. N. Engl. J. Med. 355, Hirschel, B., and Flanigan, T. (2009) Is it smart to continue to study treatment interruptions? AIDS 27, Ananworanich, J., Nuesch, R., Côté, H. C., Kerr, S. J., Hill, A., Jupimai, T., Laopraynak, N., Saenawat, S., Ruxrungtham, K., and Hirschel B. (2008) Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine a Staccato trial substudy. J. Antimicrob. Chemother. 61, Vergis, E. N., Paterson, D. L., Wagener, M. M., Swindells, S., and Singh N. (2001) Dyslipidaemia in HIV-infected patients: association with adherence to potent antiretroviral therapy. Int. J. STD AIDS 12, Magalhães, M. G., Greenberg, B., Hansen, H., and Glick M. (2007) Comorbidities in older patients with HIV: a retrospective study. J. Am. Dent. Assoc. 138, Anonymous (2009) Anti-HIV agents. Treatment interruption surprisingly does not reduce heart disease risk. Treatmentupdate 21, Ferry J. A., Sohani, A. R., Longtine, J. A., Schwartz, R. A., and Harris, N. L. (2009) HHV8-positive, EBV-positive Hodgkin lymphoma-like large B-cell lymphoma and HHV8-positive intravascular large B-cell lymphoma. Mod. Pathol. 22, Ho, J. E., and Hsue, P. Y. (2009) Cardiovascular manifestations of HIV infection. Heart 95, Dybul, M., Chun, T. W., Yoder, C., Hidalgo, B., Belson, M., Hertogs, K., Larder, B., Dewar, R. L., Fox, C. H., Hallahan, C. W., Justement, J. S., Migueles, S. A., Metcalf, J. A., Davey, R. T., Daucher, M., Pandya, P., Baseler, M., Ward, D. J., and Fauci, A. S. (2001) Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: effects on virologic, immunologic, and toxicity parameters. Proc. Natl. Acad. Sci. U. S. A. 98, Dybul, M., Nies-Kraske, E., Dewar, R., Maldarelli, F., Hallahan, C. W., Daucher, M., Piscitelli, S. C., Ehler, L., Weigand, A., Palmer, S., Metcalf, J. A., Davey, R. T., Rock Kress, D. M., Powers, A., Beck, I., Frenkel, L., Baseler, M., Coffin, J., and Fauci, A. S. (2004) A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection. J. Infect. Dis. 189, Cohen, C. J., Colson, A. E., Sheble-Hall, A. G., McLaughlin, K. A., and Morse, G. D. (2007) Pilot study of a novel short-cycle antiretroviral treatment interruption strategy: 48-week results of the five-days-on, two-days-off (FOTO) study. HIV Clin. Trials 8, Ananworanich, J., Nuesch, R., Le Braz, M., Chetchotisakd, P., Vibhagool, A., Wicharuk, S., Ruxrungtham, K., Furrer, H., Cooper, D., Hirschel, B., and the Swiss HIV Cohort Study. (2003) Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial. AIDS 17, F33 F Cardiello, P. G., Hassink, E., Ananworanich, J., Srasuebkul, P., Samor, T., Mahanontharit, A., Ruxrungtham, K., Hirschel, B., Lange, J., Phanuphak, P., and Cooper, D. A. (2005) A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection. Clin. Infect. Dis. 40, Fischer, M., Hafner, R., Schneider, C., Trkola, A., Joos, B., Joller, H., Hirschel, B., Weber, R., and Gunthard, H. F., for the Swiss HIV Cohort Study (2003) HIV RNA in plasma rebounds within days during structured treatment interruptions. AIDS 17, Fischer, M., Joos, B., Hirschel, B., Bleiber, G., Weber, R., and Günthard, H. F., for the Swiss HIV Cohort Study. (2004) Cellular viral rebound after cessation of potent antiretroviral therapy predicted by levels of multiply spliced HIV-1 RNA encoding nef. J. Infect. Dis. 190, Bangsberg, D. R., Acosta, E. P., Gupta, R., Guzman, D., Riley, E. D., Harrigan, P. R., Parkin, N., Deeks, S. G.(2006) Adherenceresistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness. AIDS 20, Bangsberg, D. R., Perry, S., Charlebois, E. D., Clark, R., Roberston, M., Zolopa, A. R., and Moss, A. (2001) Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS 15, Bangsberg, D. R., Porco, T. C., Kagay, C., Charlebois, E. D., Deeks, S. G., Guzman, D., Clark, R., and Moss A. (2004) Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates. J. Infect. Dis. 190, Martin, M., Del Cacho, E., Codina, C., Tuset, M., De Lazzari, E., Mallolas, J., Miró, J.-M., Gatell, J. M., and Ribas, J. (2008) Relationship between adherence level, type of the antiretroviral regimen, and plasma HIV type 1 RNA viral load: a prospective cohort study. AIDS Res. Hum. Retroviruses 24, Müller, A. D, Myer, L, and Jaspan, H. (2009) Virological suppression achieved with suboptimal adherence levels among South African children receiving boosted protease inhibitorbased antiretroviral therapy. Clin. Infect. Dis. 48, 3 5 Received for publication October 16, Accepted for publication December 10, EFFECTIVE SHORT CYCLES OF ANTIRETROVIRAL DRUGS 1655