Scientists continue to wrestle with the question of whether combination antiretroviral therapy (ART) completely suppresses HIV replication in most recipients. The development of ultra-sensitive “single copy” viral load tests (which can measure down to 0.3 HIV RNA copies in a milliliter of blood) has revealed that most individuals with levels below 50 copies show evidence of persistent residual viral RNA. There are two potential (non-exclusive) sources: long-lived, chronically infected cells containing integrated viral DNA which produce RNA copies either intermittently or continuously—such cells would be impervious to the effects of current antiretroviral therapies—or low-level HIV replication, in which new RNA copies are produced which go on to infect other cells. In the latter case, intensifying ART with additional drugs would be predicted to reduce the amount of residual viral load and the number of cells containing integrated HIV DNA.
A slew of new papers (abstracts below) describe the results obtained in several different treatment intensification trials. The results add to the evidence that, in the majority of individuals, ongoing low-level HIV replication is not the source of residual HIV RNA, and nor is it the major driver of immune activation in individuals on ART. Most prior studies of treatment intensification have produced similar results, with just a couple of notable exceptions. In one small trial involving intensification with raltegravir there was a transient increase in a piece of HIV’s genetic code called a 2-LTR circle in around 1/3 of participants, which suggests the drug may have been blocking new rounds of infection in these individuals. Another similar trial produced evidence that the addition of raltegravir may have reduced HIV replication and immune activation in a specific part of the gut (the terminal ileum). But the preponderance of evidence now favors chronically infected cells as the primary source of residual viral load on ART, highlighting the importance of designing strategies to identify, target and eliminate this persistent HIV reservoir.
J Infect Dis. (2011) doi: 10.1093/infdis/jir667
First published online: October 21, 2011
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and Swedish Institute for Infectious Disease Control, Stockholm, Sweden
2Department of Neurology
3Department of Medicine, University of California, San Francisco
4Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Austria
Background. Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation.
Methods. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4+ and CD8+ T-cell surface antigen expression.
Results. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4+ and CD8+ T-cell activation.
Conclusions. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects.
Clin Infect Dis. (2011) doi: 10.1093/cid/cir721
First published online: October 19, 2011
Guillaume J. Besson1, Deborah McMahon1, Frank Maldarelli2, and John W. Mellors1
1Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
2National Cancer Institute, Frederick, Maryland
TO THE EDITOR—Controversy exists about whether human immunodeficiency virus type 1 (HIV-1) replication persists in patients receiving effective antiretroviral therapy. Residual viremia can often be detected in such patients by sensitive quantitative polymerase chain reaction assays, but the source of this viremia is unknown . Possibilities include ongoing cycles of HIV-1 replication, long-lived HIV-1–infected cells that continuously or intermittently produce virus, or both. If residual plasma viremia is derived from ongoing HIV-1 replication, intensification of an effective regimen with another potent antiretroviral drug should lower viremia. Such treatment intensification studies have been conducted with different classes of antiretroviral agents (nucleoside reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, protease inhibitors, and the integrase inhibitor raltegravir), and none has shown reduction in residual viremia [ …
JAIDS Journal of Acquired Immune Deficiency Syndromes:
POST ACCEPTANCE, 11 November 2011
Gandhi, Rajesh T.; Coombs, Robert W.; Chan, Ellen S.; Bosch, Ronald J.; Zheng, Lu; Margolis, David M.; Read, Sarah; Kallungal, Beatrice; Chang, Ming; Goecker, Erin A.; Wiegand, Ann; Kearney, Mary; Jacobson, Jeffrey M.; D'Aquila, Richard; Lederman, Michael M.; Mellors, John W.; Eron, Joseph J.; for the AIDS Clinical Trials Group (ACTG) A5244 team
Background: Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication.
Methods: We previously reported the outcome of a randomized, placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies/mL that showed no effect on residual viremia measured by single copy assay (SCA). We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication: 2-LTR HIV-1 circles, total cellular HIV-1 DNA and T cell activation.
Results: Of 50 patients tested, 12 (24%) had 2-LTR-circles detected at baseline. Patients who were 2-LTR-positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR-negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T cell activation.
Conclusions: In HIV-1-infected individuals on effective antiretroviral therapy, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.
POST ACCEPTANCE, 14 November 2011
Chege, Duncan; Kovacs, Colin; La Porte, Charles; Ostrowski, Mario; Raboud, Janet; Su, Desheng; Kandel, Gabor; Brunetta, Jason; Kim, Connie; Sheth, Prameet M.; Kaul, Rupert; Loutfy, Mona R.
Background: Highly active antiretroviral therapy (HAART) dramatically reduces plasma HIV-1 viremia. However, despite completely suppressive HAART, it has been suggested that low-levels of viral replication may persist in the gut mucosa and elsewhere in individuals on long-term HAART.
Objective: We conducted a double-blind randomized, placebo-controlled trial (RCT) evaluating whether intensification of HAART in long-term virologically suppressed individuals with raltegravir is associated with a reduction in the level of proviral HIV-1 DNA in CD4+ T cells in blood and the sigmoid colon (gut).
Methods: Long-term (>4 years) virologically suppressed HIV-infected individuals on standard HAART were randomized 1:1 in a double-blind fashion to receive raltegravir (400mg twice/day) or placebo for 48 weeks. After week 48, all participants were treated with raltegravir to week 96. Blood and sigmoid biopsies were sampled and the frequency of CD4+ T cells carrying HIV-1 proviral DNA was determined.
Results: 24 study patients were recruited. At 48 weeks, no difference was apparent between participants receiving raltegravir or placebo in blood HIV-1 proviral levels (p=0.62), CD4+ T cell counts (p=0.25) and gut proviral loads (p=0.74). Similarly, prolonged raltegravir intensification up to week 96 had no further effect on both blood and gut HIV-1 proviral loads and blood CD4+ T cell counts.
Conclusion: In long-term virologically suppressed patients on standard HAART, intensification with raltegravir did not result in further decay of CD4+ T cells carrying HIV-1 proviral DNA in either the blood or gut after 48 or 96 weeks of therapy, or in any increase in CD4+ T cell counts.