Chlorproguanil-dapsone-artesunate versus chlorproguanil-dapsone: a randomized, double-blind, phase III trial in African children, adolescents, and adults with uncomplicated Plasmodium falciparum malaria.

This multi-center, randomized, parallel-group, double-blind, double-dummy study compared the efficacy and safety of chlorproguanil-dapsone-artesunate (CDA) and chlorproguanil-dapsone (CPG-DDS) in the treatment of falciparum malaria in Africa (Burkina Faso, Ghana, Mali, Nigeria). Six hundred patients (>or= 1 year of age) received CDA 2.0/2.5/4.0 mg/kg, and 292 CPG-DDS 2.0/2.5 mg/kg, once daily for 3 days. Day 28 parasitologic cure rate (polymerase chain reaction [PCR]-corrected, per-protocol population) was 89.1% (416/467) for CDA, non-inferior but also superior to CPG-DDS, 83.0% (176/212) (treatment difference 6.1%; 95% confidence interval [CI] 0.3, 11.9). Glucose-6-phosphate dehydrogenase (G6PD) genotype was available for 844/892 (95%) patients. Occurrences of a composite hemoglobin safety endpoint (hemoglobin drop >or= 40 g/L or >or= 40% versus baseline, hemoglobin < 50 g/L, or blood transfusion) were CDA 13/44 (30%), CPG-DDS 7/24 (29%) in G6PD-deficient patients versus CDA 4/448 (< 1%), CPG-DDS 6/221 (3%) in G6PD-normal patients. No deaths occurred. CDA was more efficacious than CPG-DDS. However, the hemolytic potential in G6PD-deficient patients does not support further development of CDA.

Selection of drug-resistant HIV-1 during the early phase of viral decay is uncommon in treatment-naïve patients initiated on a three- or four-drug antiretroviral regimen including lamivudine.

Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n = 43), triple (n = 14) or dual (n = 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or four-drug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine + PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy.

Predictors of virological outcome and safety in primary HIV type 1-infected patients initiating quadruple antiretroviral therapy: QUEST GW PROB3005.

BACKGROUND: Initiation of antiretroviral therapy during primary human immunodeficiency virus (HIV)-1 infection may confer long-term benefit. METHODS: After initiation of zidovudine, lamivudine, abacavir, and amprenavir therapy in patients in the QUEST cohort, predictors of virological outcome, virological and immunological changes, and adverse events were evaluated over 48 weeks. RESULTS: One hundred forty-eight patients started antiretroviral therapy during primary HIV-1 infection with < or =3 bands on Western Blot (median plasma HIV-1 RNA load, 5.4 log copies/mL; median CD4 cell count, 517 cells/mm(3)). By week 48, 36% of patients had stopped treatment or were lost to follow-up. Among the 115 patients receiving follow-up care at week 48 (102 of whom were receiving antiretroviral therapy), the median viral load decrease was -5.4 log copies/mL (interquartile range [IQR], -6.4 to -3.9 log copies/mL), and the median increase in CD4 cell count was 147 cells/mm(3) (IQR, -1 to 283 cells/mm(3)); 84.2% of patients had a viral load < or =50 copies/mL, and 44.7% of patients had a viral load < or =3 copies/mL. The median cell-associated RNA level decreased from 3.4 log copies/million PBMCs (IQR, 2.9-4.1 log copies/million PBMCs) to 0.8 log copies/million PBMCs (IQR, 0.5-1.4 log copies/million PBMCs), and the median cell-associated DNA level decreased from 2.8 log copies/million PBMCs (IQR, 2.4-3.0 log copies/million PBMCs) to 1.6 log copies/million PBMCs (IQR, 1.2-1.9 log copies/million PBMCs); 33.3% of patients had an undetectable RNA level, and 9.5% of patients had an undetectable cell-associated DNA level. The median CD8(+)/CD38(++) T cell count decreased from 459 cells/mm(3) (IQR, 208-974 cells/mm(3)) to 33 cells/mm(3) (IQR, 19-75 cells/mm(3)). Baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were independent inverse predictors for reaching a viral load < or =3 copies/mL. Eighty-three patients experienced a serious adverse event (median duration of an adverse event, 15 days).Conclusions. Initiation of antiretroviral therapy during primary HIV-1 infection was associated with very significant antiretroviral activity and a decrease in immune activation. Lower baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were predictive of achieving a viral load < or =3 copies/mL.

Early immune activation in gut-associated and peripheral lymphoid tissue during acute HIV infection.

OBJECTIVE: To study innate and adaptive immune responses in gut-associated lymphoid tissue (GALT) as well as peripheral lymphoid tissue (pLT) obtained from individuals with acute HIV-1 infection syndrome. DESIGN: The expression of chemokines [regulated upon activation: normal T cell expressed/secreted (RANTES), macrophage-inflammatory protein (MIP) 1alpha/beta], cytokines (IL-1beta, TNF-alpha, IL-12, IL-4, IL-10, IL-2, IFN-gamma) and cytotoxic effector molecules (granzyme A, perforin) and cell marker (CD8) were analysed at the single cell level in GALT and pLT of patients experiencing acute HIV-1 infection (day -3 to 48 days from onset of acute symptoms). RESULTS: Substantial pro-inflammatory immune responses (TNF-alpha, IL-1beta, IL-12) and expansion in the CD8 T-cell population were noted in both compartments compared with uninfected controls. This was associated with an early increased expression of beta-chemokines (RANTES, MIP-1alpha/beta) and granzyme, but not with an increase in the expression of perforin. The upregulation of IL-2, IL-12 and IL-4 was noted in both pLT and GALT, whereas IL-10 expression was mainly increased in GALT. CONCLUSION: Taken together, these findings demonstrate that there was a broad and early immune activation in GALT and pLT during acute HIV-1 infection. The relative lack of perforin expression in both GALT and pLT, however, questions the functional efficacy of the observed immune activation in generating cytotoxic T cells that were able to eliminate HIV-infected cells.

Impact of therapeutic immunization on HIV-1 viremia after discontinuation of antiretroviral therapy initiated during acute infection.

BACKGROUND: Treatment strategies that would induce durable virological control of human immunodeficiency virus (HIV)-1 in the absence of continued antiretroviral therapy (ART) are highly desirable.METHODS. We assessed, in a randomized, double-blind, placebo-controlled trial, whether the addition of therapeutic vaccines (ALVAC-HIV [vCP1452] or ALVAC-HIV and Remune) to ART initiated during acute infection could increase the probability of having a plasma viral load

Presence of HIV-1 neutralizing IgA antibodies in primary HIV-1 infected patients.

The initial control of viral replication during primary HIV-1 infection is dominated by CD8+ T-cell mediated responses. Neutralizing IgG to autologous virus is first detected in serum weeks after this response when the viraemia has already declined. However, the mucosal and systemic HIV-1 neutralizing IgA response during primary HIV-1 infection in patients treated with HAART has not been studied previously. The presence of HIV-1 neutralizing IgA antibodies in serum (n=10 patients) and semen (n=6 patients) samples was tested against a laboratory adapted HIV-1 isolate and against primary HIV-1 isolates, representing different clades and phenotypes. The patients received HAART during the study period and were followed from primary HIV-1 infection and up to 72 weeks. Overall, HIV-1 neutralizing IgA activity could be demonstrated in serum from 5 of 10 primary HIV-1 infected patients at inclusion, although the response was restricted to only 1 of the 4 tested isolates. In semen samples, HIV-1 neutralizing IgA activity was seen in 2 of 5 patients against at least 1 of the HIV-1 isolates. In conclusion, a restricted but early neutralizing IgA response can be detected in serum and semen in primary infected patients treated with HAART.

Brief but efficient: acute HIV infection and the sexual transmission of HIV.

BACKGROUND: We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual transmission of HIV. METHODS: We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. RESULTS: Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8-10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%-24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. CONCLUSIONS: Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals.

Suppression of leukemia inhibitor factor in lymphoid tissue in primary HIV infection: absence of HIV replication in gp130-positive cells.

BACKGROUND: Leukemia inhibitor factor (LIF), a member of the interleukin-6 cytokine family, has recently been shown to inhibit HIV-1 replication both in vivo and in vitro. OBJECTIVE: LIF and its corresponding receptors gp130 and LIF receptor-alpha (LIFR-alpha) were studied in lymphoid tissue (LT) to reveal potential systemic immunoregulatory effects during the course of HIV-1 infection. METHODS: LIF, gp130, LIFR-alpha and HIV-1 replicating cells were identified at the single cell level by immunohistochemistry and quantified by computerized in situ imaging in tonsil and lymph nodes biopsies (LT) from patients with primary HIV-1 infection (PHI), chronic HIV-1 infection (cHI), long-term non-progressors (LTNP) and HIV-1 seronegative controls. RESULTS: LIF and its receptors, gp130 and LIFR-alpha were significantly (P < 0.005) upregulated in LT from PHI patients as compared with HIV-1 seronegative controls. Expression of LIF in cHI was comparable to LIF levels in HIV-1 seronegative controls whereas LTNP showed significantly reduced LIF expression (P < 0.05). LIF receptors, gp130 and LIFR-alpha were significantly upregulated in cHI (P < 0.005) but downregulated in LTNP (P < 0.05 and P < 0.005, respectively). LIF expressing cells could be demonstrated in LT 2 days after onset of acute retroviral syndrome. LIF expression was evident in CD3, CD4 and CD8 cells. Furthermore, high plasma viral load was associated with high expression of LIF in LT. Finally, no HIV-1 replication could be found in CD4 gp130-positive cells in PHI. CONCLUSIONS: LIF, gp130 and LIFR-alpha showed increased expression in LT from patients with PHI. Furthermore, HIV-1 replication did not occur in cells expressing the LIF signaling receptor, gp130, indicating that LIF may be associated with control of HIV-1 replicating cells in vivo.

Low levels of perforin expression in CD8+ T lymphocyte granules in lymphoid tissue during acute human immunodeficiency virus type 1 infection.

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) responses are detectable shortly after the acute phase of HIV infection, but they cannot control viral replication and prevent development of chronic immune suppression. This article describes a defect in the coexpression of perforin in granzyme A-positive CD8(+) T cells in lymphoid tissue from patients with acute HIV infection and a reduction in the perforin-dependent nuclear translocation of granzyme A. Furthermore, intracellular levels of HIV DNA and RNA found in lymphoid tissue were higher (10-100 times) than those found in blood, and blood samples showed more-coordinated cellular perforin/granzyme A expression. This suggests that mechanisms inhibiting CTL-mediated cytotoxicity are operative in lymphoid tissue early in the course of HIV infection.

Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection.

BACKGROUND: Dendritic cells (DC) are target cells for HIV-1 and play a key role in antigen presentation and activation of T cells. OBJECTIVE: To characterize interdigitating DC in lymphoid tissue (LT) with regard to maturation, expression of cytokines and co-stimulatory molecules in HIV-1-positive patients. METHODS: DC were characterized by immunohistochemistry and in situ imaging in LT from patients with acute HIV-1 infection (aHI), antiretroviral treated patients, long-term non-progressors/slow progressors with HIV-1 infection (LTNP/SLP), patients with AIDS, HIV-1-negative controls and patients with acute Epstein-Barr virus (EBV) infection. RESULTS: A significant increase of interdigitating DC expressing CD1a, S-100b, CD83 and DC-SIGN was found in LT from patients with aHI (P < 0.02). The co-stimulatory molecules CD80 and CD86 were, however, only partially upregulated and the complete parafollicular network found in acute EBV infection was not generated, despite increased expression of interleukins 1alpha, 1beta, 12; interleukin 1alpha receptor antagonist; interferon alpha; and CD40 expression. LTNP/SLP and treated aviremic subjects had increased frequency of interdigitating DC, albeit lower than in aHI, and low expression of CD80 and CD86. In contrast, patients with AIDS had fewer DC and reduced cytokine expression in LT. CONCLUSIONS: In the early phase of HIV-1 infection, there was a migration of DC to LT comparable to that found in acute EBV infection. The infiltration of DC in LT in acute EBV infection was accompanied by upregulation of CD80 and CD86 expression, which did not occur in aHI. This co-stimulatory defect in aHI may have an impact on the development of HIV-1-specific T cell immunity.

Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection.

OBJECTIVES: To monitor changes in the numbers of CD8 lymphocytes expressing the activated CD38++ phenotype in peripheral blood samples from patients with primary HIV infection (PHI) treated with highly active antiretroviral therapy (HAART). METHODS: Zidovudine, lamivudine, abacavir and amprenavir were initiated during PHI as part of the Quest study. Absolute numbers of CD8+/CD38++ T cells were determined using three-colour flow cytometry, and plasma viral load (VL) was measured using the Roche Amplicor method. RESULTS: The median, pre-therapy CD8+/CD38++ T cell count was 461/mm(3)(interquartile range 216, 974) in 131 patients compared with normal control values of less than 20 cells/mm(3). Levels fell markedly in parallel with VL within the first 2 weeks of HAART initiation, to a median of 47 cells/mm(3) at 28 weeks (median 436 cell decline; P < 0.001). At that time, 80% of patients had a VL less than 50 copies/ml, and 16.3% of all patients had less than 20 CD8+/CD38++ T cells/mm(3). A continued decrease in CD8+/CD38++ T cell count occurred in 67.2% of patients whose VL was maintained below 50 copies/ml (median change from first to last value -18 cells/mm(3); P < 0.001). CONCLUSION: After the initiation of HAART in PHI, CD8+/CD38++ lymphocytes declined rapidly in parallel with VL, and allowed for a normalization of CD8+/CD38++ T cell numbers in a subset of patients at week 28. Cell numbers continued to decline in patients who maintained VL below 50 copies/ml, indicating that the CD8+/CD38++ T cell count may represent a marker of residual viral replication when VL falls below detectable levels after HAART intervention.