Short-term anti-HIV activity of the combination of didanosine and hydroxyurea

The synergistic action of hydroxyurea with some other antiretroviral drugs led us to evaluate the effect of therapy with the combination of didanosine and hydroxyurea in HIV-1-infected patients. We aimed to assess the anti-HIV activity of therapy with this combination by measuring variations in viral load and in CD4 cell counts. We also evaluated the potential side effects of this drug combination in HIV-1-positive patients with advanced disease. A total of 15 HIV-1-seropositive homosexual men with a mean baseline CD4 cell count of 149 cells/mm3 (range: 1-430 cells/mm3) were recruited to the study, and received didanosine (200 mg) plus hydroxyurea (500 mg) twice daily for 12 weeks. Ten patients were didanosine naive and five had previously received didanosine (for > 3 months). The combination therapy was well tolerated, although grade 2-3 alopecia appeared in four patients who had very low CD4 cell counts (< 50 cells/mm3). No significant variation in renal, hepatic and pancreatic functions occurred. A significant reduction in the plasma HIV-1 RNA (> 0.5 logs) was observed in seven of ten patients naive to didanosine after weeks 4 and 12 of the study; five of these patients had a decrease in plasma HIV-1 RNA of > 1.5 logs, with two having a decrease of > 2.0 logs. The viral load became undetectable (below 200 copies/ml) in three patients. The patients whose plasma HIV-1 RNA levels were not significantly reduced by the combination therapy had a higher baseline viral load. CD4 cell counts did not increase significantly in most patients. We observed a better response in those patients who had virus of the non-syncytium-inducing phenotype. In conclusion, hydroxyurea in combination with didanosine was well tolerated and led to a reduction in viral load mainly in patients who were initially naive to didanosine.     

Results of the ALBI trial: a randomized comparison of stavudine/didanosine, zidovudine/lamivudine and alternating treatment in antiretroviral-naive patients

In the ALBI trial, 151 antiretroviral-naive patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 10,000 to 100,000 copies/ml and CD4 cell counts > or = 200 cells/mm3 received 24 weeks of treatment with stavudine/didanosine (n=51), zidovudine/lamivudine (n=51) or stavudine/didanosine for 12 weeks followed by zidovudine/lamivudine (n=49). Baseline plasma HIV-1 RNA and CD4 cell counts were comparable in the treatment groups. The mean decrease in plasma HIV-1 RNA at 24 weeks in the stavudine/didanosine group (2.26 log10) was significantly greater than that in either the zidovudine/lamivudine group (1.26 log10) or the alternating treatment group (1.58 log10) (P<0.0001 for both). Proportions of patients with plasma HIV-1 RNA level <500 copies/ml (91% vs 42% and 60%) and <50 copies/ml (47% versus 4% and 9%) were significantly greater in the stavudine/didanosine group (P<0.001 for pairwise comparisons). Stavudine/didanosine was associated with a mean increase in CD4 cell count (124 cells/mm3) significantly greater than that in the zidovudine/lamivudine group (62 cells/mm3, P<0.01) and comparable to that in the alternating group (118 cells/mm3). All study regimens were well tolerated. These findings, indicating superiority of stavudine/didanosine over zidovudine/lamivudine in virological and immunological response over 24 weeks, suggest that the combination should be considered as a basis for highly active antiretroviral therapy.     

Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy

Primary HIV-1 infection causes extensive immune activation, during which CD4(+) T cell activation supports massive HIV-1 production. We tested the safety and the immune-modulating effects of combining cyclosporin A (CsA) treatment with highly active antiretroviral therapy (HAART) during primary HIV-1 infection. Nine adults with primary HIV-1 infection were treated with CsA along with HAART. At week 8, all patients discontinued CsA but maintained HAART. Viral replication was suppressed to a comparable extent in the CsA + HAART cohort and in 29 control patients whose primary infection was treated with HAART alone. CsA restored normal CD4(+) T cell levels, both in terms of percentage and absolute numbers. The increase in CD4(+) T cells was apparent within a week and persisted throughout the study period. CsA was not detrimental to virus-specific CD8(+) or CD4(+) T cell responses. At week 48, the proportion of IFN-gamma-secreting CD4(+) and CD4(+)CCR7(-) T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. In conclusion, rapid shutdown of T cell activation in the early phases of primary HIV-1 infection can have long-term beneficial effects and establish a more favorable immunologic set-point. Appropriate, immune-based therapeutic interventions may represent a valuable complement to HAART for treating HIV infection.     

CD4 T cell measurements in the management of antiretroviral therapy--A review with an emphasis on pediatric HIV-infected patients

The measurement of both the percentage (in pediatric patients aged less than 5 or 6 years) and the absolute number of circulating CD4+ T cells remains the single most important parameter for establishing prognosis and determining when to treat HIV-1 infected infants. The predictive power of CD4+ T cell measurements in HIV-1 infected individuals has resulted in robust guidelines from numerous agencies on the use of CD4+ T cell measurements ranging from pretreatment evaluations to the initial assessment and monitoring of therapeutic responses and treatment failures. The increase in availability of HIV-1 antiretroviral drugs in resource limited setting has led to the urgent need to develop systems and technologies for the accurate and cost-effective measurement of CD4+ T cells. The establishment of standardized guidelines for antiretroviral therapy (including CD4 testing) along with significant advancements in the development of structured access to health care, centralized CD4 testing programs, improved quality assurance programs, and inexpensive CD4 measurement technologies are making CD4 testing more universally available. Recent evidence suggests that a CD4/CD8 ratio of less than 1 may provide a reliable marker of presumptive HIV-1 infection in HIV-1 exposed infants. This review will summarize the current guidelines for the use of CD4 testing in HIV-1 infected infants and the potential for the CD4:CD8 ratio to be used as a surrogate of HIV-1 infection in resource limited settings.     

Didanosine plus stavudine with or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Swiss HIV Cohort Study

A total of 144 human immunodeficiency virus (HIV)-infected patients (mean CD4 cell count, 367 cells/mm3) were included in a double-blind placebo-controlled trial testing the efficacy on surrogate markers of HIV progression of the combination didanosine (2',3'-dideoxyinosine or DDI) plus stavudine (2',3'-didehydro-2',3'-dideoxythymidine or D4T) with or without hydroxyurea. The primary end point was a reduction of HIV RNA levels to below 200 copies/ml after 12 weeks of treatment. The results showed that the triple combination was associated with a more profound decrease in HIV RNA with an increased proportion of patients with viraemia < 200 copies/ml. This effect persisted for the majority of the patients after a 48 week follow-up. In contrast, the increase in CD4 cell counts was less in patients treated with hydroxyurea because of lymphopenia, and adverse events were more frequent in hydroxyurea-treated patients. In conclusion, the addition of hydroxyurea consistently improved the antiviral activity of the didanosine/stavudine combination over a 48 week follow-up. Increased toxicity and decreased effect on CD4 cell counts might inspire caution.     

Improvement in immune function due to treatment with indinavir despite severe immune deficiency

To study the virological, immunological and clinical effects of the protease inhibitor indinavir in human immunodeficiency virus (HIV)-infected patients with CD4 counts < 50 cells/mm3, indinavir was added to prior treatment with nucleoside analogues in a prospective open-label study in 23 HIV-infected patients with median CD4 count of 10 cells/mm3 and median serum HIV-1 RNA load of 27,508 copies/ml. Addition of indinavir induced a decrease in HIV-1 RNA levels to < 400 copies/ml in 15 patients that was maintained until week 36 of the study in 8 (35%) patients. The median increase in CD4 cell counts was 92 cells/mm3 (range 55-258 cells/mm3) and in CD8 counts was 245 cells/mm3 (range 51-1552 cells/mm3) at week 30. The treatment induced a significant CD8 T cell expansion, consisting in the first 6 weeks of predominantly memory CD45RO+ cells and followed by expansion of naive cells from week 12 on, and a significant decrease in the proportion of activated CD8/CD38 cells. In addition, significant increases in T cell proliferation following stimulation with phytohaemagglutinin and significant decreases in the rates of spontaneous apoptosis of CD4+ and CD8+ T cells were observed. In conclusion, the addition of indinavir induced restoration of both memory and naive CD8 T cells. Corresponding evidence of improving T cell function, as assessed by enhanced lymphoproliferative capacity and diminished propensity to undergo apoptosis, provides evidence for treatment-induced regeneration of immune function even in patients with severe immunodeficiency.     

Simplification therapy with once-daily didanosine, tenofovir and efavirenz in HIV-1-infected adults with viral suppression receiving a more complex antiretroviral regimen: final results of the EFADITE trial

BACKGROUND: High pill burden and side effects often impact on the long-term success of highly active antiretroviral therapy (HAART), which has led clinicians to search for more convenient regimens. Patients and methods: A prospective, multicentre, open, comparative study in which HIV-1-infected patients on HAART and with plasma HIV-1 RNA <50 copies/ml for longer than 6 months were switched to tenofovir, didanosine and efavirenz (QD arm) or remained on the same treatment regimen (control arm). Patients with grade 4 toxicities or plasma HIV-1 RNA values repeatedly >1000 copies/ml discontinued the study. RESULTS: A total of 390 patients were included in the trial (309 in the QD arm and 81 in the control arm). The main baseline characteristics were well balanced between groups. In the QD arm, 41% of patients received high (standard) didanosine doses and 59% received reduced doses. At 12 months, plasma HIV-1 RNA <400 copies/ml was attained in 66% of QD patients and 73% of controls in the intent-to-treat (ITT) analysis (P=NS). However, the number of individuals with HIV-1 RNA <400 copies/ml in the QD arm was 56% versus 71% when comparing the use of high versus low didanosine doses (P=0.007). Treatment discontinuation occurred in 87 QD cases (28%) and 17 controls (21%). Twenty QD individuals (6.5%) and 2 controls (2.5%) discontinued because of virological failure (P=NS). The median CD4+ cell count change at 12 months was -26 and +27 cells/microl in QD patients and controls, respectively (P=0.001). In individuals who attained HIV-1 RNA <400 copies/ml, CD4+ cell changes were -25 and +15 cells/microl in QD patients and controls, respectively (P=0.001). Moreover, CD4+ cell declines in the QD arm were significantly greater in patients taking high versus low didanosine doses (-59 versus -15 cells/microl; P=0.04). The lipid profile improved significantly in the QD arm, particularly in patients who were on protease inhibitors prior to simplification. CONCLUSIONS: Simplification to didanosine-tenofovir-efavirenz provides a virological suppression rate at 12 months similar to that seen in patients who do not change therapy, as long as low didanosine doses are administered. Decreases in CD4+ cell levels in patients in the QD arm (especially decreases seen with high didanosine doses) and dyslipidaemias along with less convenient pill burden and schedules in controls were the main long-term concerns for each option.     

The dissociation between virological and immunological responses to HAART.

While HAART allows for the reconstitution of immune functions in most treated HIV patients, discrepant responses including failure to achieve a significant increase in circulating CD4+ T cells despite undetectable plasma viral loads (pVL), or a good immunological response while not reaching undetectable viremia, may occur. Thus, to evaluate the incidence of and risk factors for discrepant responses to HAART, we conducted a retrospective study of all 446 patients treated with HAART between 1 January 1998 and 31 August 2004 in our HIV unit. CD4+ T cell counts and pVL values at baseline and end of study were parameters of the type of response. Within a mean follow-up period of 33 months, discrepant immunological and virological responses occurred in even 50% patients. Of these, 174 (39%) did not have a rise in CD4+ T cells to above 400 per microl despite a good virological response (type 1 dissociation), while 49 (11.0%) had a rise in the CD4+ T cell count to at least 200 per microl but their pVL was not undetectable (type 2 dissociation). The risk factors for immunological failure despite an undetectable pVL were baseline CD4+ T cells below 100 per microl (OR 1.44, 95%CI 1.02-2.03) and HAART composed of three NRTIs (OR 1.92, 95%CI 1.35-2.73), while usage of two NRTIs in combination with PI(s) (OR 0.36, 95%CI 0.26-0.49), as well as simultaneous usage of all three drug classes (OR 0.37, 95%CI 0.26-0.53) were shown to be protective. The usage of PI-containing HAART regimens was protective against type 2 dissociation (OR=0.40, 95%CI 0.19-0.83). Importantly, there were no differences in the survival of HAART-treated patients irrespective of the type of response.     

Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection

We analyzed at clonal level the functional profile of circulating or skin-infiltrating T lymphocytes from two individuals infected with the human immunodeficiency virus type 1 (HIV-1), suffering from a Job's- like syndrome (eczematous dermatitis, recurrent skin and sinopulmonary infections, and hypergammaglobulinemia E) and showing virtually no circulating CD4+ T cells. Most of the CD3+ T cell clones generated from both patients were CD4- CD8+ TCR alpha beta +. The others were CD4- CD8- TCR alpha beta + which exhibited reduced mRNA expression for the CD8 molecule or no mRNA expression for either CD4 or CD8 molecules. The great majority of both CD4- CD8+ and CD4- CD8- did not produce interferon (IFN) gamma and exhibited reduced cytolytic activity. Rather, most of them produced large amounts of both interleukin (IL) 4 and IL-5 and provided B cell helper function for IgE synthesis. These data suggest that a switch of cytolytic CD8+ T cells showing a Th1-like cytokine secretion profile to cells that make Th2-type cytokines, exhibit reduced cytolytic potential, and provide B cell helper function can occur in the course of HIV-1 infection. These cells may contribute to the reduced defense against viral infections and intracellular parasites and account for the elevated IgE serum levels, eosinophilia, and the allergic-like clinical manifestations seen in a proportion of HIV-1-infected individuals.     

CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection

Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Valpha24-Vbeta11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Valpha24(+) T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4(+) T cells. Furthermore, resting CD4(+) NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4(+) subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4(+) NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.