Didanosine Monotherapy Research Articles

Activity, Safety, and Immunological Effects of Hydroxyurea Added to Didanosine in Antiretroviral-Naive and Experienced HIV Type 1-Infected Subjects: A Randomized, Placebo-Controlled Trial, ACTG 307

We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy.

Activity, Safety, and Immunological Effects of Hydroxyurea Added to Didanosine in Antiretroviral-Naive and Experienced HIV Type 1-Infected Subjects: A Randomized, Placebo-Controlled Trial, ACTG 307

We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine (ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200–700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy.

HIV biological variability unveiled: frequent isolations and chimeric receptors reveal unprecedented variation of coreceptor use.

To follow the evolution of coreceptor use in HIV-1-infected individuals with varying rates of disease progression. The coreceptor use of 278 sequential HIV-1 isolates from 23 individuals was tested by infection of two human cell lines, U87.CD4 and GHOST(3), expressing CD4 and CCR1, CCR2b, CCR3, CCR5, CXCR4, CXCR6 or BOB. Differences in coreceptor use were further dissected by testing chimeric coreceptors constructed by exchanging successively larger parts of CCR5 for corresponding regions of CXCR4. Three patterns of coreceptor use were distinguished: no evolution, evolution to CXCR4 use, and fluctuation. No evolution with stable CCR5 use (R5 phenotype) was linked to slow progression over 8-10 years in four patients. CXCR4-using virus was present from the onset (five patients) or appeared during clinical progression in all other patients, while taking zidovudine or didanosine monotherapy. The fluctuating pattern of coreceptor use, defined as reappearance of virus with R5 phenotype, was observed in five patients and, interestingly, followed initiation of highly active antiretroviral therapy in three of these. Monotropic R5 or X4 viruses were more selective in chimeric receptor use than R5X4 or multitropic viruses. Most importantly, the efficiency of chimeric receptor use increased over time. The increase in efficiency of chimeric receptor use allows a new interpretation of evolution of HIV-1 coreceptor use. Evolution could be a continuous process that may lead to changes in the way a coreceptor is used, with the potential of profound alteration in signalling at that receptor.

HIV biological variability unveiled

Objective: To follow the evolution of coreceptor use in HIV-1-infected individuals with varying rates of disease progression. Methods: The coreceptor use of 278 sequential HIV-1 isolates from 23 individuals was tested by infection of two human cell lines, U87.CD4 and GHOST(3), expressing CD4 and CCR1, CCR2b, CCR3, CCR5, CXCR4, CXCR6 or BOB. Differences in coreceptor use were further dissected by testing chimeric coreceptors constructed by exchanging successively larger parts of CCR5 for corresponding regions of CXCR4. Results: Three patterns of coreceptor use were distinguished: no evolution, evolution to CXCR4 use, and fluctuation. No evolution with stable CCR5 use (R5 phenotype) was linked to slow progression over 8–10 years in four patients. CXCR4-using virus was present from the onset (five patients) or appeared during clinical progression in all other patients, while taking zidovudine or didanosine monotherapy. The fluctuating pattern of coreceptor use, defined as reappearance of virus with R5 phenotype, was observed in five patients and, interestingly, followed initiation of highly active antiretroviral therapy in three of these. Monotropic R5 or X4 viruses were more selective in chimeric receptor use than R5X4 or multitropic viruses. Most importantly, the efficiency of chimeric receptor use increased over time. Conclusion: The increase in efficiency of chimeric receptor use allows a new interpretation of evolution of HIV-1 coreceptor use. Evolution could be a continuous process that may lead to changes in the way a coreceptor is used, with the potential of profound alteration in signalling at that receptor.

T69D/N pol mutation, human immunodeficiency virus type 1 RNA levels, and syncytium-inducing phenotype are associated with CD4 cell depletion during didanosine therapy.

The contribution of virologic and host factors to CD4 cell depletion associated with human immunodeficiency virus (HIV) type 1 was evaluated in children drawn from a larger efficacy trial of 2 doses of didanosine (ddI) monotherapy (Pediatric AIDS Clinical Trials Group 144). Thirty children, half with stable CD4 cell counts (non-progressors) and half with a marked decline in CD4 cells (progressors), were studied during 60-72 weeks of ddI therapy. The children were matched for age and CD4 cell counts at study entry. Three viral parameters, syncytium-inducing phenotype, higher virus load, and mutation in HIV-1 pol encoding the T69D/N mutation, were associated with disease progression. Disease progression was not associated with mutations in the reverse-transcriptase gene previously associated with resistance to ddI (L74V, K65R, or M184V). The selection of the T69D/N mutation in children with HIV-1 disease progression during ddI therapy suggests that this mutation confers a fitness advantage to the virus that may include resistance to ddI.

A Randomized Study of the Safety and Antiretroviral Activity of Hydroxyurea Combined with Didanosine in Persons Infected with Human Immunodeficiency Virus Type 1

This randomized open-label trial of human immunodeficiency virus type 1-infected persons compared safety and efficacy for 38 patients receiving hydroxyurea/didanosine combination therapy with findings in 42 persons given didanosine monotherapy for 12 weeks, followed by 12 weeks of hydroxyurea/didanosine combination therapy for all patients. Week 12 on-treatment group comparisons showed a mean decrease in virus load between hydroxyurea/didanosine versus didanosine groups of -0.93 versus -0.74 log10 copies/mL (P=.20); a higher percentage of the hydroxyurea/didanosine group below the assay's detection limit (500 copies/mL), 29% versus 7% (P=.017); and median change in CD4 cells for the hydroxyurea/didanosine versus didanosine group of 0 versus 43 cells/mm3 (P=.045), although median change in CD4 percentage was similar (0.9% vs. 1.2%, P=.64). Week 24 virus load reductions and CD4 cell changes were similar in both groups. Intent-to-treat and on-treatment analyses showed similar results. The hydroxyurea/didanosine combination was well tolerated.

Avoid didanosine monotherapy in paediatric HIV infection

Avoid didanosine monotherapy in paediatric HIV infection

Low doses of zidovudine plus didanosine are less effective than higher doses of didanosine monotherapy: a randomized trial in patients pretreated with zidovudine.

OBJECTIVE: To compare the clinical efficacy and tolerance of didanosine (ddl) monotherapy with low-dose zidovudine/didanosine (AZT/ddl) therapy among HIV-infected patients previously treated with AZT. METHODS: A randomized controlled trial was carried out of ddl 400 mg daily versus AZT/ddl 300/200 mg daily among patients with CD4 cell counts </=350 mm3 and prior AZT treatment for at least 16 weeks. Fifty eight patients received ddl monotherapy and 66 combined treatment. RESULTS: Patients were similar with respect to demographic, clinical and laboratory characteristics, and prior AZT treatment. Median duration of follow-up was 17.3 months. In the ddl group, 20 patients (34%) discontinued treatment because of toxicity, compared to 19 (29%) in the AZT/ddl group (p=0.38). There was no statistically significant difference in CD4 change between the two groups. In the ddl group, 16 patients (28%) developed a clinical endpoint (death or AIDS-defining opportunistic infection), compared to 33 (50%) in the combined therapy group (relative risk 1.8; 95% confidence interval 1.1-2.9; p=0.01). CONCLUSIONS: For fairly advanced AZT-pretreated patients, monotherapy with ddl was clinically and statistically superior to the low-dose AZT/ddl combination in preventing AIDS-defining illness and death. When access to drugs is limited, e.g. in under-resourced countries, combining available drugs and reducing dosage may be less effective than a single drug at the conventional dosage.

Didanosine. An update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease.

Didanosine is a dideoxynucleoside analogue, which is phosphorylated to the active metabolite dideoxyadenosine triphosphate (ddATP) intracellularly. At therapeutic concentrations, ddATP inhibits HIV replication by inhibiting HIV reverse transcriptase. Didanosine is established as a first-line treatment for patients with HIV disease and has recently been shown to be superior to zidovudine monotherapy in the treatment of patients with intermediate-stage HIV infection. In clinical practice, however, combination regimens of antiretroviral drugs are generally considered preferable to monotherapy as first-line treatment for most patients with HIV disease. Importantly, 2 large multicentre studies have demonstrated that combination therapy with didanosine and zidovudine was more effective than zidovudine monotherapy in delaying disease progression and death in patients with intermediate or advanced HIV disease. In other comparative studies, improvements in surrogate markers of HIV disease were generally greater in patients who received combination therapy than in recipients of antiretroviral drug monotherapy. Improvements in surrogate markers were also observed in children who received didanosine monotherapy in several clinical trials. Although the efficacy of combination antiretroviral drug therapy has not yet been investigated extensively in children, a combination regimen of didanosine and zidovudine was well tolerated and achieved beneficial effects on surrogate markers if HIV disease. In addition, preliminary findings of a larger study have shown that disease progression was delayed in children and adolescents who received didanosine plus zidovudine combination therapy compared with those receiving zidovudine monotherapy. Didanosine has a tolerability profile that is distinctly different from that of zidovudine. In particular, didanosine exhibits only minimal haematological toxicity when administered either as a single agent or in combination with zidovudine. The most serious dose-limiting adverse effects associated with didanosine treatment are peripheral neuropathy and pancreatitis. In conclusion, didanosine monotherapy is an effective treatment of HIV infection. However, combination antiretroviral therapy is the optimal treatment strategy for most patients, and didanosine is now firmly established as a component of combination antiretroviral drug regimens for the first-line treatment of patients with HIV disease.

Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype.

Eight zidovudine-experienced subjects received zidovudine and didanosine for 30 weeks followed by 30 weeks of didanosine monotherapy. At study entry, plasma from 4 subjects had human immunodeficiency virus RNA pol T215Y/F mutant and 4 had codon 215 wild type. All 8 subjects had non-syncytium-inducing virus phenotype. Sustained 10-fold decreases in plasma RNA levels were seen only in subjects who initially had 215 wild type RNA, despite the development of a T215Y/F mutation during combination therapy. Virologic and immunologic benefits were maintained in this group with didanosine monotherapy. No subject developed a pol L74V codon mutation. Significant differences in plasma virus load and CD4 cell responses were seen in this zidovudine-didanosine combination pilot study relative to codon 215 genotype.

Zidovudine Resistance Reverse Transcriptase Mutations during Didanosine Monotherapy

Zidovudine Resistance Reverse Transcriptase Mutations during Didanosine Monotherapy

Development of resistance to zidovudine (ZDV) and didanosine (ddl) in HIV from patients in ZDV, ddl and alternating ZDV/ddl therapy

To study development of phenotypic and genotypic resistance against zidovudine (ZDV) and didanosine (ddI) during 24 months of mono- and monthly alternating therapy. Forty-six patients, not previously treated with antiretroviral drugs, were included in the study. ZDV and ddI sensitivity were determined in a biological assay based on production of HIV antigen in cultures of CD4+ lymphocytes. The ZDV-associated mutations at codon 41 and 215, and the ddI-associated mutation at codon 74 of the reverse transcriptase (RT) gene were analysed using selective polymerase chain reaction on DNA from peripheral blood mononuclear cells. The biological phenotype [syncytium-inducing (SI)/non-SI(NSI)] of the viral isolates was assessed using a MT2 assay. Of the patients, 82% in ZDV therapy and 73% in alternating therapy developed phenotypic resistant HIV [median inhibitory concentration (IC50) > 0.1 microM]. Patients treated for 1 year with ddI (monotherapy or alternating) had significant higher ddI IC50 values than patients in ZDV monotherapy. During ZDV and alternating therapy, 67 and 75% of the patients, respectively, developed mutations in RT codon 41, whereas 83 and 75%, respectively, developed mutations in codon 215. In patients treated with ddI, 60% developed mutations in codon 74, whereas none of the patients in either alternating ZDV/ddI or ZDV therapy developed this mutation. Forty-six per cent of the patients had SI HIV at start of therapy. Four patients switched from SI to NSI during either ZDV, ddI or alternating therapy. Faster development of resistance was associated with the SI phenotype. No difference in either phenotypic ZDV or ddI resistance, or genotypic ZDV resistance could be demonstrated during monotherapy or monthly alternating ZDV/ddI therapy, whereas genotypic ddI resistance (mutation in RT codon 74) only were detected in patients in ddI monotherapy. In addition, we found that development of phenotypic and genotypic resistance was faster in patients harbouring SI isolates, and that switches from SI to NSI during therapy was independent of the type of therapy.

Development of zidovudine resistance mutations in patients receiving prolonged didanosine monotherapy.

Human immunodeficiency virus type 1 (HIV-1) isolates from 2 patients who received didanosine (ddI) monotherapy for > 2 years were analyzed for reverse transcriptase (RT) mutations by sequencing of proviral DNA from peripheral blood mononuclear cell cultures. One patient was otherwise antiretroviral-naive; the other had received zidovudine for 5 months before beginning ddI therapy. Isolates obtained from both patients before initiation of ddI monotherapy were free of HIV-1 RT mutations associated with zidovudine or ddI resistance. However, after prolonged ddI monotherapy, mutations associated with zidovudine resistance (M41L, D67N, K70R, and/or T215Y) were detected in HIV-1 isolates from both patients. There was no evidence that surreptitious use of zidovudine or technical artifact caused these findings. This observation suggests that prolonged ddI monotherapy may decrease the efficacy of subsequent zidovudine therapy in some patients.

Randomized Study of Didanosine Monotherapy and Combination Therapy With Zidovudine in Hemophilic and Nonhemophilic Subjects With Asymptomatic Human Immunodeficiency Virus-1 Infection

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.

Transient High Titers of HIV-1 in Plasma and Progression of Disease

Periodic quantitative HIV-1 plasma cultures were performed on 28 seropositive individuals who had CD4 cells < or = 300/mm3 and who were enrolled in three clinical trials testing the efficacy of didanosine versus zidovudine monotherapy. Most plasma cultures were negative or of low titer (1-100 tissue culture infective dose/ml of plasma), but there were 14 instances of high-titered plasma viremia (> or = 1,000 tissue culture infective dose/ml of plasma) seen in 11 individuals. These peaks in plasma culture titers were significantly associated either with rapidly decreasing CD4 cell numbers or with CD4 cells already < 50/mm3. In addition, patients who experienced these episodes of high-titered plasma viremia were more apt to have clinical complaints of fever, rash, flu-like illness, and/or opportunistic infection and also the syncytium-inducing HIV-1 phenotype and progression of disease.

Early and Prolonged Decrease of Viremia in HIV-1-Infected Patients Treated with Didanosine

Fourteen patients previously treated with zidovudine were monitored for laboratory parameters and clinical events during 1 year after introduction of didanosine (ddI) monotherapy. Proviral human immunodeficiency virus type 1 (HIV-1) copy numbers (cell-associated DNA) and concentration of free virions (viremia) were determined using a semiquantitative polymerase chain reaction (PCR). High levels of circulating virus were detected in all patients (range, 17 to 5,934 x 10(3)/ml of serum). Within 4 weeks of therapy, a decrease of viremia (60 to 98%) was observed in nine patients. After 1 year of treatment, eight of these nine patients still had decreased viremia when proviral HIV DNA was decreased or stable, and CD4+ lymphocytes were stable or higher in seven of these eight patients. Antiviral effect was more pronounced in the six patients with CD4+ > 100/mm3 at entry, five of them belonging to the subgroup of the seven responding patients as compared to two of eight patients with CD4+ < 100/mm3. Clinical events in this small group were not statistically correlated with virologic parameters; however, responding patients had a tendency to stabilize or gain weight. This study suggests that measurement of viremia deserves further study as a marker of antiviral efficacy and might predict, even at 4 weeks, the beneficial potential of ddI.

Identification of drug-related genotypic changes in HIV-1 from serum using the selective polymerase chain reaction

We attempted to detect drug-related HIV-1 pol gene mutations by selective polymerase chain reaction (PCR) using both proviral DNA and viral RNA isolated from patients (pts) with AIDS or ARC receiving antiretroviral therapy. Peripheral blood mononuclear cell (PBM)-associated proviral DNA and serum-derived viral RNA were obtained from eight patients before and after receiving an alternating regimen of AZT and ddC for 15–41 months or ddI monotherapy for 12–26 months. These specimens were examined for the presence of mutations at positions 70, 74, 215 and 219. We noted that selective PCR results can be ambiguous depending on the quantity of DNA template employed. We, therefore, used the minimal quantity of DNA templates that yielded evaluable PCR products in this study. For all the eight pairs of pre- and post-therapy proviral DNA samples, selective PCR results agreed with independently determined nucleotide sequences. Results of reverse transcription of serum-derived viral RNA followed by selective PCR differed in some cases from those using the proviral DNA. In particular, the use of serum viral RNA appeared to allow earlier detection of changes in drug-related mutations than the use of PBM-associated proviral DNA. We conclude that (i) selective PCR using the minimum and sufficient number of PBM-associated proviral DNA and serum viral RNA copies successfully detects the presence of known pol gene mutations; (ii) drug-related mutations may be distinguished earlier in virions in serum (or plasma) than in proviral DNA in PBM; and (iii) quantification of HIV-1 prior to selective PCR may be an important component in monitoring the therapy of HIV-1 infection.

High-level resistance to zidovudine but not to zalcitabine or didanosine in human immunodeficiency virus from children receiving antiretroviral therapy

Human immunodeficiency virus type 1 (HIV-1) isolates from children receiving long-term therapy with an alternating regimen of zidovudine and zalcitabine, or with didanosine monotherapy, were evaluated for resistance to zidovudine, zalcitabine, and didanosine, and for mutations known to be associated with zidovudine or didanosine resistance. HIV-1 from four of six patients receiving zidovudine with zalcitabine developed high-level resistance to zidovudine. A mutation in the HIV-1 reverse transcriptase that is highly associated with zidovudine resistance was identified in all four zidovudine-resistant posttherapy isolates. In contrast, none of the HIV-1 isolates from the seven patients receiving didanosine developed high-level resistance to this agent, despite the identification of a didanosine-associated mutation in six of these posttherapy isolates, although small decreases in sensitivity to didanosine were observed. These results indicate that nucleoside analog-associated mutations in HIV-1 occur frequently in children receiving long-term antiretroviral therapy and that alternating combination therapy does not prevent the development of resistance to zidovudine. They also suggest that there may be differences in the degree of resistance conferred by mutations that result from therapy with different nucleoside analogs. These findings underscore the need for studies to define the clinical importance of these mutations, and for treatment strategies to overcome the emergence of viral resistance in vivo.

Didanosine (ddI) and zidovudine (ZDV) susceptibilities of human immunodeficiency virus (HIV) isolates from long-term recipients of ddI

Thirty HIV isolates, obtained from 15 patients before and after receiving single drug therapy with didanosine (ddI), were examined for sensitivity to ddI and zidovudine (ZDV) using a peripheral blood mononuclear leukocyte (PBML)-based assay. Fourteen of the patients had ARC, one had AIDS and 12 had received previous therapy with ZDV. After a median of 1 year of ddI therapy, isolates were significantly less sensitive to ddI than were isolates obtained prior to therapy ( P = 0.03). A decrease in ddI sensitivity was observed in ten of the 15 isolate pairs. In contrast to ddI susceptibilities, sensitivity to ZDV increased over the same period of time ( P = 0.03). Additional isolates were obtained from four patients who received ddI monotherapy for 2 years. Three of these isolates demonstrated no change in ddI sensitivity compared to baseline. No correlation could be made in this study between development of decreased ddI sensitivity and serum p24 levels, CD4 counts, or clinical outcome. Decreased ddI sensitivity occurs frequently among HIV isolates obtained from long-term recipients of ddI. This decreased sensitivity is modest in degree and is of unknown clinical significance.