Structured treatment interruptions as a potential alternative therapeutic regimen for HIV-infected patients: a review of recent clinical data and future prospects

Franco Lori*, Andrea Foli and Julianna Lisziewicz

Research Institute for Genetic and Human Therapy (RIGHT) at IRCCS Policlinico S. Matteo, P. le Golgi, 2-27100 Pavia, Italy, and 2233 Wisconsin Avenue, Suite 503, Washington, DC 20007, USA


    Abstract
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
Highly active antiretroviral therapy (HAART) allows for substantial control of HIV replication in vivo, and has caused a significant decline in morbidity and mortality rates among patients. However, eradication of the virus from the body is not possible. Therefore, HAART necessarily becomes a life-long treatment and this is associated with several problems: (i) the high cost of therapy; (ii) increased frequency of drug-related side effects; (iii) viral resistance; and (iv) poor patient adherence to the treatment. Based on these considerations, among other alternative strategies, structured treatment interruptions (STI) have been proposed with the potential object-ive of inducing immune-mediated control of HIV replication in HIV-infected patients. The available clinical data indicate that STI might increase HIV-specific, cell-mediated immune responses in patients treated during primary HIV infection; however, it does not seem to have the same effect in patients treated during chronic infection. Nevertheless, in chronically infected patients STI might limit drug-related side effects by decreasing exposure to drugs, without influencing the efficacy of the therapy. In addition, recent data suggest a possible role for immune-modulations such as hydroxyurea and therapeutic vaccines as adjuvant therapies for limiting viral rebound in these patients. Preliminary indications suggest that there is reduced hope for STI as a salvage therapy. Finally, it is important to stress that no controlled, randomized studies of STI have been held in humans, and it is not possible to evaluate fully the clinical impact of such a strategy. Therefore, clinicians and patients should avoid using STI outside the setting of controlled clinical trials.


    Introduction
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
Highly active antiretroviral therapy (HAART) has been proved to substantially ameliorate the management of HIV infection. By suppressing virus replication, decreasing morbidity and mortality rates have been observed among HIV-infected patients.13 However, the main goal of HAART, i.e. the eradication of the virus, has not been achieved. Without any other viable therapy, HAART should be maintained for the rest of a patient’s life. This prospect generates several problems, such as the high cost of the therapy, drug-related side effects, decreased adherence and the emergence of viral resistance. Furthermore, HAART does not induce reconstitution of HIV-specific immune responses, and upon therapy discontinuation all patients experience rapid viral rebounds and loss of CD4 T lymphocytes.4,5

Therefore, there is an unmet need for alternative therapies to continuous HAART. Along with the development of additional drugs, the possibility of using different administration schedules has been hypothesized. In particular, structured treatment interruptions (STI), consisting of alternating on and off cycles of HAART, have recently been investigated in: (i) primary HIV infection (PHI); (ii) chronic infection; (iii) virological failure; and (iv) in conjunction with adjuvant therapy. In this review, clinical data on the use of STI in these different settings are presented.


    STI during PHI: the concept of autovaccination
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
Shortly after HIV infection, patients still have a relatively intact immune system with vigorous HIV-specific immune responses. The main goal of STI is to induce long-term control of HIV replication by sustaining these HIV-specific immune responses. The idea of STI originated from the report of the Berlin patient who after two consecutive on and off cycles of therapy was able to control viral replication associated with a strong specific cell-mediated immune response.6 New excitement about STI came from a study in which eight patients were treated during PHI. Control of HIV replication was established after therapy interruption in all these patients,7 together with a progressive increase in the quality and quantity of HIV-specific immune responses. Recently, the entire HIV-specific cytotoxic T lymphocyte (CTL) response in one patient from this cohort has been investigated.8 During acute infection CTL response targeted two epitopes, after STI the response covered 27 epitopes. This observation suggests that CTL responses can be broadened by STI during acute infection. In the meantime our group reported the first randomized, controlled STI study.9 Acutely infected monkeys were treated with a fixed STI schedule or continuous HAART regimen. The STI resulted in controlled viral rebound and increased simian immunodeficiency virus-specific immune responses, indicating that STI were responsible for inducing therapeutic ‘autovaccination’ and immune control after treatment interruption. Additional data on the immunological effects of STI were presented recently.10 Twelve patients were treated with HAART within 90 days from symptoms onset for at least 1 year before starting STI. In all patients CTL response substantially increased during STI, and CD4 proliferative response became detectable in the majority of patients. However, viral control without therapy was attained only in one-third of the patients. This suggests that very early treatment, before seroconversion,11 is needed to maximize STI success during PHI.

Autovaccination is therefore based on the concept of inducing controlled viral rebound, thus utilizing the autologous virus as antigen to stimulate HIV-specific immune responses (Figure 1). Two strategies might be envisaged. (i) To resume drug treatment as soon as HIV reappears in the plasma. This would require frequent monitoring of the viral load, and might be applied in research settings involving a limited number of patients. (ii) To cycle HAART according to a pre-determined fixed schedule, selecting a schedule that will not allow uncontrolled viral replication (such as a 1–3 week HAART interruption), thus avoiding frequent viral load determinations. This strategy would make STI feasible for studies involving large numbers of patients, and applicable in clinical practice.



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Figure 1. STI during acute infection. During primary HIV infection treatment interruption induces controlled HIV replication. The autologous virus acts as antigen to stimulate HIV-specific immune responses (not yet damaged at this stage) resulting in ‘autovaccination’.

 

    STI during chronic infection
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
PHI lasts only a few weeks, and diagnosis of HIV infection is problematic during this period. After complete seroconversion the patient is already chronically infected11 and the immune system is probably then permanently damaged.1215 Pilot studies conducted to evaluate the efficacy of STI in inducing control of HIV replication in patients with chronic HIV infection have shown that autovaccination is problematic in this setting. In fact, viral control was established in only a limited number of patients.1618

Figure 2 illustrates how STI do not seem to reduce the extent of viral rebound and change the viral load set-point during chronic infection. Probably, STI are not sufficient to stimulate a proper immune response in chronically infected patients,11,19,20 and the autologous virus can only transiently mobilize HIV-specific T cells. This hypothesis has been confirmed recently.8,2126 CD8 T cell responses improve during STI; however, this increase does not correlate with viral control.2123 In addition, a study evaluating CTL responses during STI in chronic infection has shown that the increase in CTL responses was probably related to the expansion of responses already present in the lymph nodes.8 It has also been shown that CD4 T cells specific for HIV antigens are more frequently infected by HIV, and an increase in the number of CD4-infected T cells was observed after STI.24 Furthermore, CD4 T cell proliferative responses were inhibited in the presence of high viraemia during STI.25,26 This might be caused by the rapid depletion of T cells during uncontrolled viral replication,27 thus limiting the ability of STI strategies to induce immune-mediated viral control during chronic HIV infection. Lack of viral control during chronic infection might also be due to changes of the viral quasi-species, and this would render immune control of viral replication increasingly problematic after each STI cycle.28,29



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Figure 2. STI during chronic infection. In patients with chronic infection STI does not induce controlled HIV replication. The autologous virus is not sufficient to elicit an effective HIV-specific immune response (already damaged by HIV at this stage).

 
Despite this, STI could still play a major role during chronic infection. The present objective of STI during chronic HIV infection is to ensure long-term drug-mediated control of HIV by decreasing HAART-associated toxicity without jeopardizing the efficacy and cost effectiveness of the treatment. Based on this aim, a group at the National Institutes of Health recently attempted a 1 week on and 1 week off fixed-schedule STI strategy clinical trial.30 Even without immunological benefits, in these patients there was substantial control of HIV replication, no evidence of development of resistance, along with a significant decrease in cholesterol and triglyceride levels. These data support the concept that chronically infected patients treated with STI could still enjoy a substantial reduction in cost, and a reduction of drug-related toxic side effects due to the relief from their continuous medication regimen.


    STI after virological failure
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
During virological failure the rationale for STI is to restore drug sensitivity. STI might induce a change in the prevalent quasi-species from the drug resistant to the wild-type, thus hypothetically reverting the virus to a sensitive phenotype.31 However, it is not clear whether these changes have any long-term efficacy, or whether damage to the immune system (loss of CD4) outweighs the gains; also reversion to the wild-type requires at least 8 weeks of therapy interruption,31 and this could be associated with a deep decline in CD4 counts and AIDS-related events. Thus far, STI in patients after virological failure have not been too encouraging.31,32 However, the immunological follow-up of an STI study in salvage therapy31 showed that patients with relatively low viral load (<3.5 log) had significantly higher HIV-specific immune responses compared with patients with higher viraemia, indicating a possible role for the immune system in controlling HIV replication in these patients.33


    ‘Adjuvant’ therapy for STI
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
A very interesting and novel concept is whether the time free from viral rebound during STI in chronic infection could be increased by using adjuvants. These therapies could enhance the HIV-specific immune responses, and certain immune-modulant drugs have been considered for this purpose. Potential immune-modulants are cytokines, such as interleukin-12 and granulocyte-macrophage colony-stimulating factor, or drugs with potential immune-modulant properties, such as mycophenolic acid and hydroxyurea.34,35 The use of mycophenolic acid during STI was recently evaluated.36 Fifteen patients were randomized to receive or not 4 months of mycophenolic acid after 12 months on HAART. Only three of nine patients had to restart therapy in the mycophenolic group compared with four of five patients in the control group; however, there was no significant difference between the viral load values of the two groups. Preliminary results in patients treated with hydroxyurea are quite encouraging and indicate that continuous hydroxyurea administration during STI might limit viral rebound.37,38 Another study has shown that in chronically infected patients treated for a median of 2 years with didanosine and hydroxyurea HIV replication was controlled for as long as 8 weeks during treatment interruption.39 Finally, our group is presently conducting a clinical trial (RIGHT 901) on 60 antiretroviral drug-naive patients with chronic HIV infection randomized to receive fixed schedule STI with or without hydroxyurea. Regardless of the regimen, STI did not induce spontaneous control of HIV replication; however, hydroxyurea-treated patients did not experience the brisk fall of CD4 counts observed in those not treated with this drug.40

A very exciting possibility is represented by the potential combined strategy of STI and an HIV vaccine inducing an HIV-specific T-cell-mediated immune response. By using such a combination, autologous (by STI) and heterologous (by vaccine) viruses (as antigen) might synergize to increase HIV-specific immune responses, most likely eliciting a broader response (Figure 3). Our group and others are exploring the possibility of using HIV vaccines and STI in combination as a therapeutic technique to extend drug-free periods during the management of HIV infection. Vaccine candidates have been designed for therapeutic vaccination, such as HIV-1 Immunogen, poxvirus-based vaccines or DermaVir.4143 In addition, vaccines conceived for prevention44,45 might be tested. Autologous and heterologous antigens might indeed act synergically to enhance HIV-specific immune responses.



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Figure 3. Chronic infection: STI + therapeutic immunization. By combining STI with an HIV vaccine that induces a T-cell-mediated response, autologous and heterologous HIV antigens might synergize, thus inducing a broader and effective HIV-specific immune response. A controlled HIV replication might then be obtained, similar to that observed with STI alone during acute infection (see Figure 1).

 

    Conclusions
 Top
 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
Although preliminary reports on STI indicate the feasibility and the efficacy of this therapeutic approach, it should not be forgotten that there are inherent risks. Suspension of a successful antiretroviral therapy without proper monitoring might allow uncontrolled viral rebound, possibly inducing re-population of viral reservoirs and/or loss of CD4. During the on/off therapy cycles of STI other problems may be envisaged: potential induction and reduction of the P450 system and recurrence of acute drug-related side effects. Finally it should be mentioned that certain social factors, insurance policies and government regulations should also be considered for their influence upon patients’ overall well-being.

In our opinion, STI might represent a valid alternative to continuous HAART in acute as well as in chronically HIV-infected patients. However, the results available to date are not sufficient to recommend the use of this strategy in everyday practice, since the individual results are still unpredictable and the potential hazards are not fully known. In order to evaluate the potential of STI, and clarify the overall risk/benefit ratio, large, controlled and randomized clinical trials are necessary. Many of these trials are presently ongoing.46

Based on the above considerations, it could be hypothesized that the immune system itself might become a ‘fourth drug’ as part of the arsenal to efficiently control HIV replication. However, until further studies confirm the safety and efficacy of STI, clinicians and patients should refrain from using this therapeutic scheme. Ultimately, the use of therapeutic vaccines, or a combination of STI and therapeutic vaccines, will be a safer and more reproducible approach to induce HIV-specific immune responses in infected individuals.


    Acknowledgements
 
We would like to thank Al Ruel and Sylva Petrocchi for editorial assistance. The work was supported in part by Istituto Superiore di Sanità grant 30.C.44.


    Footnotes
 
* Corresponding author. Tel: +39-038-250-2944; Fax: +39-038-250-2988; E-mail: rightpv{at}tin.it Back


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 Abstract
 Introduction
 STI during PHI: the...
 STI during chronic infection
 STI after virological failure
 ‘Adjuvant’ therapy...
 Conclusions
 References
 
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