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HIV Persists in the Gut Despite
Long-Term HIV Therapy
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Second Study Finds that B-Cell Abnormalities Also Persist
NIH Feb 13, 2008
Even with effective anti-HIV therapies, doctors still have not been able to eradicate the virus from infected individuals who are receiving such treatments, largely because of the persistence of HIV in hideouts known as viral reservoirs. One important reservoir is the gut, where HIV causes much of its damage due to the large number of HIV target cells that reside there. These cells, known as CD4+ T cells, are largely contained in lymph nodes and patches of lymphocytes that collectively are called gut-associated lymphoid tissue, or GALT.
Because of the importance of the gut to HIV disease, scientists hoped that long-term treatment with antiretroviral drugs could eradicate HIV from the GALT. A new NIAID study, published online by The Journal of Infectious Diseases, has found that this goal seems unlikely with current antiretroviral drugs.
Tae-Wook Chun, Ph.D., of the NIAID Laboratory of Immunoregulation (LIR), Anthony S. Fauci, M.D., LIR chief and NIAID director, and their colleagues intensively studied eight patients receiving effective antiretroviral therapy for up to 9.9 years. In each of these of these individuals, therapy had consistently kept their blood levels of HIV at undetectable levels. Sensitive tests, however, detected the persistence of HIV as well as lowered CD4+ T cell levels in the GALT that did not completely rebound in response to therapy. Levels of virus were higher in the GALT than in immune cells in the blood, where HIV also was consistently found. In addition, the scientists found evidence of cross infection between the GALT and the lymphocytes in the blood, suggesting that one reason the virus persists in the blood is because of ongoing cycles of replication in the GALT. The authors conclude that any possibility of further lowering or eliminating viral reservoirs likely will require more powerful drug regimens to stop the low levels of ongoing viral replication originating in the GALT. The development of such regimens is an important goal of NIAID-supported research.
A second study from the Fauci laboratory, conducted by Susan Moir, Ph.D., and her colleagues and also published online by The Journal of Infectious Diseases provides additional insights into the effects of antiretroviral therapy on the HIV disease process.
In most HIV-infected individuals, the virus replicates at high levels and CD4+ T-cell numbers decline. These two factors also strongly affect B cells, the cells of the immune system that make antibodies and help protect against infection. Dr. Moir and her colleagues demonstrated that prior to treatment with antiretroviral therapy, B-cell numbers in the blood of HIV-infected individuals who have been infected for several years are low, and the B cells also include several dysfunctional subsets. After one year of effective treatment with antiretroviral therapy, B-cell numbers returned to normal, and several of the dysfunctional subsets also normalized. However, those B-cells that provide long-term protection against infection--so-called memory B cells--did not return to normal levels. Dr. Moir notes that these findings strengthen the notion that while antiretroviral therapy improves many aspects of immune function in HIV-infected individuals, important deficiencies remain, especially in individuals who wait several years before initiating therapy. More studies are needed to determine whether early initiation of antiretroviral therapy helps restore the immune system more completely.
ARTICLES:
TW Chun et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. The Journal of Infectious Diseases DOI: 10.1086/527324 (2008).
S Moir et al. Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. The Journal of Infectious Diseases DOI: 10.1086/526789 (2008).
Anthony S. Fauci, M.D., NIAID director and chief, NIAID Laboratory of Immunoregulation (LIR); Tae-Wook Chun, Ph.D., NIAID LIR; and Susan Moir, Ph.D., NIAID LIR, are available to comment on these articles.
CROI Abstract 693
Interrupted ART of Acute Compared with Recent HIV Infection: Final Results of ACTG 371
Paul Volberding*1, E Connick2, R Bosch3, E Aga3, C Pettinelli4, M Hirsch3, M Vogler5, S Little6, L Demeter7, and AIDS Clinical Trials Group
1Univ of California, San Francisco, US; 2Univ of Colorado, Denver, US; 3Harvard Univ, Boston, MA, US; 4NIAID, NIH, Bethesda, MD, US; 5New York Univ, New York, US; 6Univ of California, San Diego, US; and 7Univ of Rochester, NY, US
Background: Therapy in early HIV infection followed by treatment interruption may enhance viral control and allow deferral of chronic therapy. We hypothesized that individuals treated during acute HIV-1 infection (usual estimated infection in prior 14 days) would have better viral control than those treated during recent HIV-1 infection (usual estimated infection in prior 14 to 180 days) 24 weeks after treatment interruption.
Methods: Subjects entered a phase II multicenter prospective non-randomized trial of ritonavir-boosted protease inhibitor-based antiretroviral therapy stratified by acute infection vs recent infection with predefined criteria. If subjects sustained ≥52 weeks of viral suppression <50 copies/mL, treatment was interrupted. If rebound viremia occurred (> 5000 copies/mL on 3 consecutive visits or >50,000 copies/mL on 2 visits), a second treatment course was initiated and, if successful in suppressing viremia was again followed by treatment interruption. The primary study endpoint was maintaining a plasma viral load <5000 copies/mL for 24 weeks following first or second treatment interruption.
Results: Between July 1999 and September 2003, 121 subjects were enrolled at 15 AIDS Clinical Trials Group (ACTG) sites. Of the 121 enrolled subjects, 115 were men, the median age was 34 years; 84 were white, and 114 had no history of injection drug use. Median CD4+ T cell count at baseline was 535 (25th to 75th percentile, 422 to 753) cells/mm3 and median baseline viral load was higher in the AI (210,000 copies/mL) than in the recently infected (43,000 copies/mL) group. Baseline resistance mutations were approximately 15% in each group. The 73 subjects (28 acute infections, 45 recent infections) who entered the first treatment interruption form the primary endpoint analysis population. The primary endpoint of sustained virologic suppression <5000 copies/mL was achieved in 29 (40%) of the 73. There was no significant difference (p = 0.81) in virologic success between those with acute infections (43%, 95%CI 24 to 63%) and those with recent infections (38%, 95%CI 24 to 53%). Successful outcomes were more common in the combined trial population with baseline viral load <100,000/mL 22 of 46 (48%) than in those with >100,000/mL, 7 of 27 (26%). Treatment was in general well tolerated.
Conclusions: Of subjects treated during acute or recent infection, 40%sustained a viral load <5000 copies/mL after 24 weeks of treatment interruption. There was no significant difference between the 2 groups. Even earlier intervention may be required to improve outcome of primary HIV infection.
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