Impact of Raltegravir Intensification on HIV-1-infected Subjects With Complete Viral Suppression Under Monotherapy With Protease Inhibitors
Condition: HIV-1 Infection
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a pilot, proof of concept, open-label clinical trial, to assess the extend of
      persistent viral reservoir and the level of immune activation in patients receiving
      suppressive treatment with protease inhibitors.

      40 Chronically HIV-1 infected subjects, receiving monotherapy with ritonavir-boosted
      lopinavir or darunavir for at least 12 months with plasma viremia below 50 copies HIV RNA per
      ml, and CD4 T-cell counts greater than 500 cells/mm3 will be included.

      The total duration of the study will be 48 weeks: 12 weeks for patients' inclusion, 24 weeks
      of follow-up once the last patient is included, and 12 weeks for data analysis.
    

Detailed description: 
      AIDS continues to be a major global health priority. Although important progress has been
      achieved in preventing new HIV infections and in lowering the annual number of AIDS-related
      deaths, the number of people living with HIV worldwide continued to grow in 2008, reaching an
      estimated 33.4 million. AIDS-related illnesses remain one of the leading causes of death
      globally and are projected to continue as a significant global cause of premature mortality
      in the coming decades: an estimated 3 million new HIV infections and 2 million deaths due to
      AIDS-related illnesses occurred worldwide in 2008 (UNAIDS, report 2009).

      In contrast to the failed attempts at developing a vaccine against HIV, efforts to provide
      drug therapies stand as a great success. More than 25 agents have been approved thus far, and
      the right combinations can suppress replication of the virus, often keeping blood levels so
      low as to be undetectable by standard tests. These powerful drug combinations, collectively
      termed highly active antiretroviral therapy, HAART, have prolonged life and health in
      countless infected individuals.

      Although life expectancy of HAART-treated people in developed countries has significantly
      improved, treatment has to be carefully observed to avoid virus rebound, what will happen in
      only in a few days after treatment withdrawal (13). Moreover, long-term treatment is not
      exempt from complications, including the continuous likelihood of developing drug resistance
      and the induction of significant metabolic disturbances as a consequence of drug toxicities,
      which will clinically impact on the future health of the HIV-infected patient, including
      hyperlipidaemia, lipodystrophy, metabolic syndrome, cardiovascular disease and type 2
      diabetes. Finally, the cost of full HIV-1 treatment implementation should not be disregarded.
      Only in Catalunya, the annual cost in antiretroviral approaches the 300 million Euros.

      Guidelines for the use of antiretrovirals for HIV-1 infection recommend combining at least
      three agents. However, toxicities, cost, and the complexity of such regimens warrant the
      search for other options. Boosted protease inhibitor monotherapy is one of the appealing
      options being investigated.

      Different clinical trials have evaluated the efficacy of boosted protease inhibitor
      monotherapy in several clinical settings: maintenance therapy of HAART-suppressed subjects
      (1-3, 12), salvage regimens (10) and first-line treatment (4, 7-9). Monotherapies with
      boosted lopinavir or darunavir have been largely investigated in maintenance and
      induction-maintenance strategies, showing that they are able to maintain viral suppression in
      a high proportion of patients. Thus, both Darunavir/ritonavir DRV/r and Lopinavir/ritonavir
      LPV/r are accepted options for monotherapy regimens when triple therapy is not possible.

      To determine the role for low-level replication in maintaining HIV infection, our group has
      recently exploited the unique effect of Raltegravir on viral replication (6). This integrase
      inhibitor blocks integration of viral linear cDNA into genomic host cell DNA. Under normal
      conditions, in the absence of raltegravir, a small proportion of the linear cDNA is
      circularized by host DNA repair enzymes to form episomes with one or two copies of the viral
      long terminal repeat(LTR)(1-LTR or 2-LTR circles). We reasoned that if there was persistent,
      ongoing low-level viral replication in patients on antiretroviral therapy, raltegravir
      administration should result in a measurable increase in 2-LTR circles in their blood, as
      happened. Furthermore, the 2-LTR-positive subjects receiving raltegravir showed marked
      decreases in CD8+ T-cell activation markers, providing what may be the first in vivo
      demonstration that ongoing immune activation is attributable, in part, to ongoing, albeit
      low-level, viral replication.

      It seems likely that the contribution of each mechanism to maintaining HIV infection varies
      from person to person and is dependent on multiple variables, including genetics, development
      of resistance, concurrent infections, viral strain, stage of disease and antiretroviral
      regimen. In fact, among patients receiving raltegravir in the study, the main difference
      between the 2-LTR-positive and 2-LTR-negative groups was the antiretroviral regimen used: a
      total of 61% of patients in the 2-LTR-positive group was on a protease inhibitor-containing
      regimen at the time raltegravir was added, compared to 19% of the 2-LTR-negative group (P =
      0.011). It is possible that the presence of three reverse transcriptase inhibitors in
      protease inhibitor-sparing regimens reduces the probability of formation of the linear cDNA
      precursor to episomal cDNA. It is also possible that active replication occurs in anatomic
      compartments that are less accessible to protease inhibitors or that pharmacodynamic
      variability of protease inhibitors contributes to this observation.

      To further explore the previous observations, we have designed a pilot trial in which
      patients that have been on boosted protease inhibitor single-agent strategy with suppressive
      plasma viremia by standard assays would have their treatment temporary intensified with
      raltegravir. This should provide further insights in the level of residual viral replication
      and immune-affectation of patients on boosted protease inhibitor monotherapy.
    

Intervention name(s): Isentress® (Raltegravir, 400 mg every 12 hours); Isentress® (Raltegravir, 400 every 12 hours)
Intervention type(s): Drug; Drug
Intervention description(s): Lopinavir/r 200/50 mg every 12 hours + Raltegravir 400 mg every 12 hours; Darunavir/rit 800/100 mg every 24 hours + Raltegravir 400 mg every 12 hours
Other intervention name(s): N/H; N/H
Intervention MeSH terms: Raltegravir Potassium
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV-1; protease inhibitors; integrase inhibitors; raltegravir; viral replication; treatment intensification; viral pathogenesis; immune activation