Supervised Treatment Interruptions Research Articles

Modelling two different therapy strategies for drug T-20 on HIV-1 patients

A mathematical model describing the antiretroviral therapy of Enfuvirtide on HIV-1 patients is developed. The effect of Enfuvirtide (formerly called T-20) by impulsive differential equations is modeled by two different drug elimination kinetics, the first-order elimination kinetics and the Michaelis-Menten elimination kinetics. The model is a non-autonomous system of differential equations. For a time-dependent system, the disease-free equilibrium is mainly studied. Its stability, when the therapy is taken with perfect adherence, is obtained. To ensure the disease-free equilibrium remains stable, the analytical thresholds for dosage and dosing intervals are determined. The effects of supervised treatment interruption are also explored. It is shown that the supervised treatment interruption can be worse than no therapy at all.

Non‐medically supervised treatment interruptions among participants in a universally accessible antiretroviral therapy programme

We examined clinical outcomes, patient characteristics and trends over time of non-medically supervised treatment interruptions (TIs) from a free-of-charge antiretroviral therapy (ART) programme in British Columbia (BC), Canada. Data from ART-naïve individuals > or =18 years old who initiated triple combination highly active antiretroviral therapy (HAART) between January 2000 and June 2006 were analysed. Participants having > or =3 month gap in HAART coverage were defined as having a TI. Cox proportional hazards modelling was used to examine factors associated with TIs and to examine factors associated with resumption of treatment. A total of 1707 participants were study eligible and 643 (37.7%) experienced TIs. TIs within 1 year of ART initiation decreased from 29% of individuals in 2000 to 19% in 2006 (P<0.001). TIs were independently associated with a history of injection drug use (IDU) (P=0.02), higher baseline CD4 cell counts (P<0.001), hepatitis C co-infection (P<0.001) and the use of nelfinavir (NFV) (P=0.04) or zidovudine (ZDV)/lamivudine (3TC) (P=0.009) in the primary HAART regimen. Male gender (P<0.001), older age (P<0.001), AIDS at baseline (P=0.008) and having a physician who had prescribed HAART to fewer patients (P=0.03) were protective against TIs. Four hundred and eighty-eight (71.9%) participants eventually restarted ART with male patients and those who developed an AIDS-defining illness prior to their TI more likely to restart therapy. Higher CD4 cell counts at the time of TI and unknown hepatitis C status were associated with a reduced likelihood of restarting ART. Treatment interruptions were associated with younger, less ill, female and IDU participants. Most participants with interruptions eventually restarted therapy. Interruptions occurred less frequently in recent years.

Using mathematical modeling and control to develop structured treatment interruption strategies for HIV infection

The goal of this article is to suggest that mathematical models describing biological processes taking place within a patient over time can be used to design adaptive treatment strategies. We demonstrate using the key example of treatment strategies for human immunodeficiency virus type-1 (HIV) infection. Although there has been considerable progress in management of HIV infection using highly active antiretroviral therapies, continuous treatment with these agents involves significant cost and burden, toxicities, development of drug resistance, and problems with adherence; these latter complications are of particular concern in substance-abusing individuals. This has inspired interest in structured or supervised treatment interruption (STI) strategies, which involve cycles of treatment withdrawal and re-initiation. We argue that the most promising STI strategies are adaptive treatment strategies. We then describe how biological mechanisms governing the interaction over time between HIV and a patient's immune system may be represented by mathematical models and how control methods applied to these models can be used to design adaptive STI strategies seeking to maintain long-term suppression of the virus. We advocate that, when such mathematical representations of processes underlying a disease or disorder are available, they can be an important tool for suggesting adaptive treatment strategies for clinical study.

Treatment interruption to boost specific HIV immunity in acute infection

To understand the potential benefits and limitations of the treatment of acute, or primary, HIV infection followed by supervised treatment interruptions as a strategy to augment immune responses. Although this strategy led to the short-term control of virus replication after treatment interruption, follow-up data showed limited durability of control, and additional studies of short-term treatment in primary HIV infection show either a modest or no long-term benefit on CD4 cell counts and viral loads when compared with no therapy. Studies of gut-associated lymphatic tissue provide insights into the limitations of this approach because there has already been a massive destruction of the CD4 memory T-cell compartment by the time of symptomatic primary HIV infection by AIDS-associated retroviruses, which occurs before the emergence of cellular immune responses. There is currently no confirmed benefit of treatment of primary HIV infection by antiviral therapy alone in terms of disease progression and HIV-specific T-cell responses once therapy is interrupted. Supervised treatment interruption in acute HIV infection treated by antiviral therapy alone should probably not be used as a therapeutic strategy. This approach should be differentiated from early treatment itself, with or without immune augmentation, which deserves further investigation.

Reconsidering Early HIV Treatment and Supervised Treatment Interruptions

Reconsidering Early HIV Treatment and Supervised Treatment Interruptions

Limited Durability of Viral Control following Treated Acute HIV Infection

BackgroundEarly treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI), has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection.Methods and FindingsFourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79%) patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%), six (43%), and three (21%) of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria.ConclusionsThese data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low-level viremia may be difficult to achieve.

Supervised Treatment Interruptions Fail to Control HIV-1 Viremia

Supervised Treatment Interruptions Fail to Control HIV-1 Viremia

Antiretroviral resistance associated with supervised treatment interruptions in treated acute HIV infection.

We studied 14 patients acutely infected with wild-type HIV, who underwent supervised treatment interruptions after initial antiretroviral treatment including lamivudine. Lamivudine resistance mutations emerged for the first time during supervised treatment interruptions in one patient. Resistance should be monitored in supervised treatment interruptions trials, because mutations may first be detected only after therapy is interrupted.

Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses following acute HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses generated during acute infection play a critical role in the initial control of viremia. However, little is known about the viral T-cell epitopes targeted during acute infection or about their hierarchy in appearance and relative immunodominance over time. In this study, HIV-1-specific CD8+ T-cell responses in 18 acutely infected individuals expressing HLA-A3 and/or -B7 were characterized. Detailed analysis of CD8 responses in one such person who underwent treatment of acute infection followed by reexposure to HIV-1 through supervised treatment interruptions (STI) revealed recognition of only two cytotoxic T-lymphocyte (CTL) epitopes during symptomatic acute infection. HIV-1-specific CD8+ T-cell responses broadened significantly during subsequent exposure to the virus, ultimately targeting 27 distinct CTL epitopes, including 15 different CTL epitopes restricted by a single HLA class I allele (HLA-A3). The same few peptides were consistently targeted in an additional 17 persons expressing HLA-A3 and/or -B7 during acute infection. These studies demonstrate a consistent pattern in the development of epitope-specific responses restricted by a single HLA allele during acute HIV-1 infection, as well as persistence of the initial pattern of immunodominance during subsequent STI. In addition, they demonstrate that HIV-1-specific CD8+ T-cell responses can ultimately target a previously unexpected and unprecedented number of epitopes in a single infected individual, even though these are not detectable during the initial exposure to virus. These studies have important implications for vaccine design and evaluation.

Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection

To date, most studies have focused on the characterization of HIV-1–specific cellular immune responses in the peripheral blood (PB) of infected individuals. Much less is known about the comparative magnitude and breadth of responses in the lymphoid tissue. This study analyzed HIV-1–specific CD8+ T cell responses simultaneously in PB and lymph nodes (LNs) of persons with chronic HIV-1 infection and assessed the dynamics of these responses during antiretroviral treatment and supervised treatment interruption (STI). In untreated chronic infection, the magnitude of epitope-specific CD8+ T cell activity was significantly higher in LNs than in PB. Responses decreased in both compartments during highly active antiretroviral therapy, but this decline was more pronounced in PB. During STI, HIV-1–specific CD8+ T cell responses in PB increased significantly. Enhancement in breadth and magnitude was largely due to the expansion of pre-existing responses in the LNs, with new epitopes infrequently targeted. Taken together, these data demonstrate that HIV-1–specific CD8+ T cells are preferentially located in the LNs, with a subset of responses exclusively detectable in this compartment. Furthermore, the enhanced CD8+ T cell responses observed during STI in chronically infected individuals is largely due to expansion of pre-existing virus-specific CD8+ T cells, rather than the induction of novel responses.

Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection.

To date, most studies have focused on the characterization of HIV-1-specific cellular immune responses in the peripheral blood (PB) of infected individuals. Much less is known about the comparative magnitude and breadth of responses in the lymphoid tissue. This study analyzed HIV-1-specific CD8+ T cell responses simultaneously in PB and lymph nodes (LNs) of persons with chronic HIV-1 infection and assessed the dynamics of these responses during antiretroviral treatment and supervised treatment interruption (STI). In untreated chronic infection, the magnitude of epitope-specific CD8+ T cell activity was significantly higher in LNs than in PB. Responses decreased in both compartments during highly active antiretroviral therapy, but this decline was more pronounced in PB. During STI, HIV-1-specific CD8+ T cell responses in PB increased significantly. Enhancement in breadth and magnitude was largely due to the expansion of pre-existing responses in the LNs, with new epitopes infrequently targeted. Taken together, these data demonstrate that HIV-1-specific CD8+ T cells are preferentially located in the LNs, with a subset of responses exclusively detectable in this compartment. Furthermore, the enhanced CD8+ T cell responses observed during STI in chronically infected individuals is largely due to expansion of pre-existing virus-specific CD8+ T cells, rather than the induction of novel responses.

Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection

Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection

Less is more? STI in acute and chronic HIV-1 infection.

Emerging data has indicated that supervised treatment interruption (STI) of highly active antiretroviral therapy might significantly augment immune responses in HIV-1-infected patients and slow disease progression. Here the authors discuss the rationale behind STI and future directions for study.