Impact of Tamoxifen on Vorinostat-Induced Human Immunodeficiency Virus Expression in Women on Antiretroviral Therapy: AIDS Clinical Trials Group A5366, The MOXIE Trial.

BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.

Residual plasma viraemia and infectious HIV-1 recovery from resting memory CD4 cells in patients on antiretroviral therapy: results from ACTG A5173.

BACKGROUND: In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viraemia and ex vivo recovery of infectious virus from latently infected CD4 cells is uncertain. METHODS: We measured residual viraemia (HIV-1 RNA copies/ml) by single-copy assay (SCA) and the latent reservoir by infectious virus recovery from resting memory CD4 cells (infectious units per million cells [IUPM]) in patients who initiated ART. We assessed immune activation by measuring CD38 expression on T-cells. RESULTS: Ten patients who initiated ART and maintained a plasma HIV-1 RNA level < 200 copies/ml had residual viraemia and IUPM measured every 24 weeks. Five of 10 patients had longitudinal IUPM measured at weeks 24-96; the remainder had IUPM measured 1-3 times over 24-72 weeks. Analyses of 29 paired measurements revealed a positive association between level of residual viraemia and IUPM (0.56 higher log10 HIV-1 RNA copies/ml per 1 log10 higher IUPM; P = 0.005). Residual viraemia level was positively associated with CD38 density and percentage on CD8+ T-cells in concurrent samples and with pre-ART HIV-1 RNA levels. CONCLUSIONS: In patients with HIV-1 RNA levels < 200 copies/ml 24-96 weeks after initiating ART, the level of viraemia is positively associated with infectious virus recovery from resting memory CD4 cells. Whether this association persists after longer-term suppressive ART needs to be determined. If additional studies show that residual viraemia measured by SCA reflects the size of the latent reservoir in patients who have had virological suppression for longer periods of time, this could facilitate testing of potentially curative strategies to reduce this important reservoir.

Augmented HIV-specific interferon-gamma responses, but impaired lymphoproliferation during interruption of antiretroviral treatment initiated in primary HIV infection.

BACKGROUND: Antiretroviral therapy (ART) introduced during primary HIV infection followed by treatment interruption (TI) is postulated to enhance virologic control through induction of HIV-specific CD4 T cells, which foster virus-specific CD8+ T cells that suppress virus replication. This hypothesis was evaluated in 21 subjects enrolled in AIDS Clinical Trials Group 709, a substudy of AIDS Clinical Trials Group 371, which prospectively evaluated subjects who received ≥1 year of ART initiated in acute or recent HIV infection followed by TI. METHODS: Lymphoproliferation was assessed by [methyl-H] thymidine incorporation and HIV-specific CD8+ T-cell interferon-gamma responses by enzyme-linked immunospot-forming assays. Virologic success was defined as sustained viral load <5000 copies per milliliter for 24 weeks after TI. RESULTS: HIV-specific lymphoproliferative responses were detected at least once in 5 (24%) of 21 subjects, were generally transient, and were unrelated to HIV-specific interferon-gamma responses (P > 0.4). HIV-specific CD8+ interferon-gamma responses increased after 48 weeks of ART (P = 0.03), but failed to predict virologic success (P = 0.18). Compared with seronegative subjects, lymphoproliferation to Candida, cytomegalovirus, and alloantigens was similar in HIV-infected subjects during ART, but lower during TI (P ≤ 0.04). CONCLUSIONS: HIV-specific CD8+ T-cell interferon-gamma responses expand during ART following primary HIV infection, but are not related to HIV-specific lymphoproliferative responses nor virologic success. Impaired non-HIV antigen-specific lymphoproliferation associated with TI suggests this strategy could be deleterious.

A randomized trial of interleukin-2 during withdrawal of antiretroviral treatment.

In HIV-infected individuals on antiretroviral treatment with viral suppression, structured treatment interruptions are designed to allow exposure to endogenous HIV antigens and to thereby boost HIV-specific immunity. AIDS Clinical Trials Group A5132 was an exploratory 2-arm randomized trial that evaluated two 4-week treatment interruptions in combination with 2 strategies for administering interleukin-2 (IL-2): 2.0 million international units of IL-2 subcutaneously daily during the final 2 weeks of treatment interruption and the first week of treatment reinitiation (arm A), or 4.5 million international units of IL-2 subcutaneously twice a day during the first 5 days of treatment reinitiation (arm B). Twenty-one subjects with HIV-1 RNA <50 copies/mL and CD4+ T cell counts ≥300 (median 615) cells/mm(3) were randomized. The primary endpoint was the viral setpoint measured 11-12 weeks after a third treatment interruption (observed for 7 Arm A and 9 Arm B). The median HIV-1 RNA setpoints were 4.3 and 4.5 log(10) copies/mL for Arm A and Arm B, respectively; there was no evidence of a difference between arms (P = 0.50, rank-sum test, worst rank for unobserved viral setpoint). The current study, the first to evaluate IL-2 during repeated short-term treatment interruptions, revealed no evidence for augmentation of HIV immunity. Viral setpoints were similar to historical controls, emphasizing the need for new strategies to enhance HIV-specific immunity.

Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328).

BACKGROUND: Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks. RESULTS: The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm3 at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed. CONCLUSIONS: Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease. TRIAL REGISTRATION: A5051 ClinicalTrials.gov Identifier: NCT00000923.

A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024).

Strategies to limit life-long dependence on antiretroviral therapy (ART) are needed. We randomized 81 human immunodeficiency virus (HIV)-infected subjects to 4 interventional arms involving continued ART plus ALVAC vCP1452 (or placebo) with or without interleukin (IL)-2 infusions. Viral load rebound 12 weeks after ART interruption was then analyzed to assess immune control. Fifty-two subjects reached the study end point. ALVAC recipients had 0.5 log(10) lower virologic rebounds (P=.033). IL-2 plus vaccine boosted CD4(+) T cell counts (P<.001) but did not diminish viral rebound. Significant changes were not detected for HIV-specific lymphoproliferative responses in any arm. This exploratory protocol provides useful clinical data for future therapeutic immunization trial design.

A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm(-3).

Adult Clinical Trials Group Study 349 examined the immunology, virology, and safety of 40 mg/d prednisone as an adjunct to antiretroviral therapy in 24 HIV-infected subjects with >200 CD4+ T cells/mm in a randomized placebo-controlled trial. After 8 weeks, median lymphocyte and CD4+ cell numbers increased >40% above baseline values (p =.08). No effect was observed on markers of cell activation or apoptosis, although the proportion of CD28+ CD8+ T cells increased (p =.006). Prednisone inhibited monocyte TNFalpha production without affecting T-cell responses to antigens or mitogens. Two subjects assigned to prednisone were subsequently found to have asymptomatic osteonecrosis of the hip. Many questions remain regarding the role of activation-induced sequestration and apoptosis as causes of progressive CD4+ T-cell loss in AIDS. The potential role of corticosteroids as tools to examine this question will be limited by concerns regarding their toxicity; however, further studies of other agents to limit cellular activation in AIDS are warranted.