Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case-control study on 174 patients.

Oral melphalan and dexamethasone (MDex) is a standard treatment for patients with AL amyloidosis who are not eligible for stem cell transplantation at many referral centers. However, following encouraging reports on the activity of bortezomib combined with alkylators and dexamethasone, these combinations are being moved to frontline therapy. We compared the outcome of 87 patients treated with bortezomib plus MDex (BMDex) with that of 87 controls treated with MDex. Patients and controls were matched for age, cardiac and renal function and free light chain burden. A higher rate of complete responses was observed with BMDex (42 vs 19%), but this did not result in a survival improvement in the overall population. However, a significant survival advantage for BMDex was observed in patients without severe (New York Heart Association class III or IV) heart failure and with N-terminal pro-natriuretic peptide type-B <8500 ng/l. Patients treated with full-dose dexamethasone had similar response rates and survival whether they received bortezomib or not. Intermediate-risk patients who are not fit enough to receive high-dose dexamethasone are likely to take the greatest advantage from the addition of bortezomib to MDex.

Virostatics: a new class of anti-HIV drugs.

In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency.

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

Role of hydroxyurea during structured treatment interruptions.

Highly active antiretroviral therapies (HAART) represent a major advance in the treatment of HIV infection. Although with HAART a substantial suppression of viral replication can be obtained, eradication of the virus from the body cannot be achieved. Therefore, HIV-infected subjects have to be treated for the rest of their lives. Long term treatment will increase the frequency of: i) drug-related side effects; ii) onset of drug-resistant viral strains; iii) non-adherence of the patients to the treatment. Structured treatment interruptions (STI)-HAART might represent a feasible alternative and preliminary studies have shown that STI-HAART might induce immune control in patients treated in the early stage of infection. This regimen does not produce similar effects in patients treated during the chronic phase of the infection. However, there are some clinical data suggesting a possible role of hydroxyurea (HU) in inducing control of HIV replication in patients with established infection. In this manuscript in vitro and in vivo data indicating that HU might play a major role in the setting of STI-HAART will be presented.

Direct analysis of mitochondrial toxicity of antiretroviral drugs.

OBJECTIVES: Mitochondrial toxicity is a serious side-effect of antiretroviral drugs, especially nucleoside reverse transcriptase inhibitors (NRTI). An in vitro assay to predict mitochondrial toxicity of in-use and developmental NRTI would be invaluable. To test the ability of a cytofluorimetric technique to predict the mitochondrial-dependent pancreatic and hepatic toxicity we used didanosine (ddI) alone or in combination with hydroxyurea (HU). METHODS: The technique is based on the ability of the lipophilic cation JC-1 to enter selectively into mitochondria and change its colour as the membrane potential changes due to toxicity. Mitochondrial toxicity by HU and ddI was evaluated in pancreatic and hepatic human cell lines. The results were expressed as mitochondrial toxicity index (MTI), ranging from 0 to 100: the negative control was 0, and 100 indicating maximal toxicity. RESULTS: Dose-dependent pancreatic toxicity of ddI was evident after 14 days of culture (MTI 34 +/- 4 at 100 microM, 10 +/- 4 at 10 microM, 2 +/- 3 at 1 microM ddI). HU alone was not toxic (MTI 7 +/- 10 at 100 microM, 2 +/- 2 at 50 microM and 2 +/- 4 at 10 microM HU); however, HU increased the toxicity of high, but not low, concentrations of ddI. For example, the MTI of 10 microM ddI plus 50 microM HU was 54 +/- 9. Negligible mitochondrial toxicity was observed in the hepatic cell line exposed to ddI alone or in combination with HU. CONCLUSIONS: This in vitro assay might have in vivo relevance. First, ddI-related pancreatitis is dose dependent, and is reported more frequently than hepatic failure, consistent with our in vitro results. Second, patients who developed pancreatitis during randomized, controlled trials were treated with HU in combination with 400 mg ddI once daily (high peak concentration of ddI in the blood). In contrast, no pancreatitis was observed when HU was combined with 200 mg ddI twice daily (low peak concentration of ddI). These in vivo results are consistent with our in vitro observation that HU increases pancreatic cell toxicity in the presence of high concentrations of ddI. The in vitro assay described here might be used to predict the mitochondrial toxicity of other NRTI, alone or in combination.

Structured treatment interruptions to control HIV-1 infection.

Structured treatment interruptions progressively lowered the rate of viral rebound in some HIV-1 infected patients. This approach should be explored as an alternative to continuous antiretroviral therapies.

Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.

Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

Hydroxyurea toxicity combined with didanosine (ddl) in HIV-1-seropositive asymptomatic individuals.

OBJECTIVE: Hydroxyurea, a carbamate compound widely used for the treatment of myeloproliferative disorders, has been investigated in several clinical trials conducted in the setting of HIV infection, where it is given in combination regimens almost always containing didanosine (ddI). Hydroxyurea mainly acts as a ribonucleotide reductase inhibitor and can positively modulate the activity of several pyrimidine and purine analogues. Due to its inhibition of DNA synthesis, the main side-effect of hydroxyurea is represented by myelosuppression. DESIGN: The toxicity profile of hydroxyurea plus didanosine (ddI) has been investigated in 40 asymptomatic HIV-positive patients with a baseline CD4+ absolute count between 250 and 500 cells/microl. Bone marrow function tests and adverse events occurring during the trial were analyzed. RESULTS: No major toxic event according to WHO classification was registered. At the dosage of 500 mg twice a day, hydroxyurea could be safely administered for at least 40 weeks of therapy. Minimal reversible bone marrow depression was noted in 2 patients. Even though reductions observed in white blood cell count, lymphocyte count and hemoglobin were statistically significant, they did not have any clinical relevance. CONCLUSIONS: Hydroxyurea seems to be well-tolerated and devoid of severe toxicity effects when used in asymptomatic HIV-positive subjects.

Combination of a drug targeting the cell with a drug targeting the virus controls human immunodeficiency virus type 1 resistance.

Combinations of drugs targeting viral proteins have been used to limit or control drug resistance, which is the most important cause of treatment failure in HIV-1-infected individuals. We suggest an alternative approach, namely to target cellular proteins, which are less prone to mutations than viral proteins. Here we show that simultaneous inhibition of a cellular protein (by hydroxyurea) and a viral protein (by ddI) produces a consistent and sustained suppression of HIV-1 for as long as 40 weeks in the absence of virus rebound. We identified the mechanism to explain this lack of rebound: although the combination of the two drugs did not prevent the emergence of mutant viral strains resistant to didanosine (ddI) in these patients, the mutants were still sensitive to standard doses of ddI in the presence of hydroxyurea. These in vivo results were consistent with our in vitro observations: HIV-1 molecular clones resistant to ddI were rendered sensitive to this drug (at concentrations routinely achievable in vivo) after addition of hydroxyurea. This phenomenon can be explained by the observation that hydroxyurea decreases the level of dATP, the cellular competitor of ddI. A low level of dATP favors the incorporation of ddI, even if the viral reverse transcriptase is resistant to this nucleoside analog. This is a novel mechanism of control of resistance and it explains the efficacy of a treatment that is well tolerated, simple, and inexpensive.

Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy.

The pattern of mutations in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) strains that confer resistance to didanosine (ddI) was analyzed in 2 groups of patients receiving either ddI monotherapy or ddI plus hydroxyurea (HU) combination therapy. Twelve patients receiving combination therapy and 8 receiving monotherapy were tested. Combinations of ddI plus HU did not prevent the onset of mutations, which emerged in 50% of the patients in this group compared with 25% of the ddI monotherapy group. In addition, in 1 patient from the combination therapy arm, who had a limited response to the therapy, an unusual pattern of mutations was found: the insertion of 2 amino acids between residues 69 and 70, a region critical for resistance to nucleoside analogs. The higher efficacy of the combination of HU and ddI compared with that of ddI monotherapy cannot be attributed to a delayed or decreased onset of resistance to ddI.

Effects of human immunodeficiency virus and colony-stimulating factors on the production of interleukin 6 and tumor necrosis factor alpha by monocyte/macrophages.

Patients infected with human immunodeficiency virus (HIV) frequently have increased production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and these cytokines may in turn contribute to the disease pathogenesis. It has been hypothesized that secretion of these cytokines by HIV-exposed mononuclear cells or HIV-infected monocyte/macrophages (M/Ms) is the principal source of their overproduction in HIV-infected patients, and the present study was undertaken to explore this issue. We observed that in the absence of endotoxin or cytokines, M/Ms productively infected by HIV do not produce detectable IL-6 or TNF-alpha. However, granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that enhances HIV replication in M/Ms and is frequently used to propagate monocytotropic strains of HIV, can induce the relatively long-term production of IL-6 (up to 47 U/ml) and TNF-alpha (up to 47 pg/ml) by M/Ms, even in the absence of HIV. Also, HIV induced production of a relatively small (< or = 9 U/ml) quantity of IL-6 in M/Ms stimulated with macrophage-colony stimulating factor (M-CSF). Finally, while highly concentrated HIV induced production of both cytokines by either M/Ms or peripheral blood mononuclear cells (PBMCs), this production was almost completely eliminated when care was taken to avoid contamination of HIV by endotoxin. These data suggest that the excess IL-6 and TNF-alpha in HIV-infected patients does not simply result from their production by HIV-infected M/Ms and that alternative mechanisms are involved in this process.

Duodenal ulcer and Helicobacter pylori infection at high altitude: experience from southern Saudi Arabia.

OBJECTIVE: To study the clinical presentation, endoscopic features and prevalence of Helicobacter pylori in duodenal ulcer (DU) patients in southern Saudi Arabia, located 3150 m above sea level, and to compare results with those from low altitude regions of the Kingdom. METHODS: Prospective study of patients with proven DU referred for upper gastrointestinal endoscopy at Asir Central Hospital, Abha, southern Saudi Arabia over an 18-month period. RESULTS: Of 126 patients with proven DU, 72% were men and mean age was 40.4 years (range 18 to 68). Twenty-eight per cent were smokers and only 5% used nonsteroidal anti-inflammatory drugs. Thirty-eight patients (30%) presented with hematemesis or melena, and the majority had a single ulcer. Nineteen per cent of patients with dyspepsia had DU and 96% had H pylori. These results are comparable with those reported from the low altitude, warmer regions of Saudi Arabia. CONCLUSIONS: Age of patients and the male:female ratio were similar to those in developing countries. The frequency of smoking is lower than in western countries and no patient in this report consumed alcohol. High altitude did not affect the prevalence of DU or the frequency of H pylori because the results were comparable with those from the low altitude areas of the Kingdom of Saudi Arabia and other lowland developing countries. Although great socioeconomic changes have increased the incidence of heart disease, the patterns of DU and H pylori infection assume those in developing nations.

Acute upper gastrointestinal bleeding in southern Saudi Arabia.

OBJECTIVES: to study the incidence of hospitalisation, causes, and outcomes of acute upper gastrointestinal bleeding (AUGIB) in southern Saudi Arabia. DESIGN AND METHODS: prospective study of patients admitted with AUGIB to a large district hospital in Abha City, southern Saudi Arabia, between 1991 and 1993. All patients had upper endoscopy within 24 hours of admission. RESULTS: AUGIB was the indication for upper endoscopy in 240 (8.9%) of all upper gastrointestinal endoscopies (2,702). The patients' mean age was 44.3 years (SD 18.1; range 20-85 years). The annual hospital admission rate for AUGIB was calculated as 31 per 100,000 population over the age of 20. The commonest causes were oesophageal varices (30%), gastritis and erosions (25%) and duodenal ulcers (22%); gastric ulcers and malignancy were relatively uncommon. Liver cirrhosis due to hepatitis B and C viruses was the main cause of bleeding oesophageal varices. Patients with variceal bleeding were younger and had a higher mortality rate than non-variceal bleeders. CONCLUSIONS: bleeding oesophageal varices are the commonest cause of AUGIB in Saudi Arabia owing to the endemicity of viral hepatitis B and C. The mortality from both variceal and non-variceal bleeding was lower than in western countries probably because the patients are younger and because of the relative rarity of malignancy and of the consumption of non-steroidal anti-inflammatory drugs.

Hydroxyurea and didanosine is a more potent combination than hydroxyurea and zidovudine.

The in vitro and in vivo antiviral activity of hydroxyurea in combination with either zidovudine or didanosine was evaluated in primary human peripheral mononuclear cells and in a cohort of 29 asymptomatic patients infected with HIV. In vitro, hydroxyurea alone did not significantly affect HIV replication, whereas the combination of hydroxyurea with didanosine was more effective than the combination of hydroxyurea with zidovudine. Our clinical results confirmed these studies. Patients were randomly assigned to five arms (zidovudine, hydroxyurea or didanosine monotherapy, or hydroxyurea in combination with either zidovudine or didanosine) to evaluate preliminary safety and efficacy. Bone-marrow toxicity occurred in two patients treated with zidovudine plus hydroxyurea, alopecia was reported in one patient treated with hydroxyurea monotherapy, and there were no toxic effects recorded in the remaining three groups. Plasma viraemia was not influenced by hydroxyurea monotherapy, and the hydroxyurea-zidovudine combination did not give any advantage over either zidovudine or didanosine monotherapy (0.3-0.5 log decrease in plasma viraemia). In contrast, a 1.1 log drop in plasma viraemia was observed in patients treated with hydroxyurea plus didanosine, this reduction was sustained throughout the 24-week course of the treatment. Combination therapy with hydroxyurea and didanosine exhibited statistically significant improvements compared with the other therapeutic approaches. Although further clinical trials are required, these results suggest that hydroxyurea in combination with didanosine might be an effective and well-tolerated, simple and affordable, treatment for HIV infection.