Didanosine Therapy Research Articles

Prevalence of drug resistance mutations in HAART patients infected with HIV-1 CRF06_cpx in Estonia.

HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] + zidovudine [ZDV] vs. EFV + 3TC + ddI) among the HIV-1 CRF06_cpx infected subjects in Estonia. HIV-1 genomic RNA was sequenced; DRMs and amino acid substitutions were compared in 44 treatment naïve and 45 first-line NNRTI + 2 NRTI treatment failed patients consisting of EFV + 3TC + ZDV (n = 17) and EFV + 3TC + didanosine[ddI] (n = 21) therapy failed sub-populations. At least one DRM was found in 78% of treatment experienced patients. The most common NRTI mutations were M184V (80%), L74V (31%), L74I (17%), K219E (9%), and M184I (9%), NNRTI mutations were K103N (83%), P225H (14%), L100I (11%), and Y188L (11%), reflecting generally the similar pattern of DRMs to that seen in treatment failed subtype B viruses. Sub-population analysis revealed that EFV + 3TC + ddI failed patients had more DRMs compared to EFV + 3TC + ZDV failed patients, especially the ddI DRM L74IV and several additional NNRTI DRMs. Additionally, CRF06_cpx specific mutation E179V and substitutions R32K, K122E, and V200AE were also detected in treatment experienced population. After the failure of the first-line EFV + 3TC + ddI therapy HIV-1 CRF06_cpx viruses develop additional NRTI and NNRTI mutations compared to EFV + 3TC + ZDV regimen. Therefore the usage of EFV + 3TC + ddI in this subtype decreases the options for next regimens containing abacavir, and NNRTI class agents.

Intracellular Nucleotide Levels during Coadministration of Tenofovir Disoproxil Fumarate and Didanosine in HIV-1-Infected Patients

Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.

Esophageal Variceal Bleed in a HIV Patient Secondary to Non-Cirrhotic Portal Hypertension After Didanosine Use

Purpose: We present a case of a HIV patient presenting with hematemesis secondary to esophageal varices, who was subsequently found to have noncirrhotic portal hypertension (NCPH) likely secondary to previous didanosine use. A 59 year old male with a history of HIV on ART since 1985, presented to our hospital with an episode of large volume hematemesis, and pre-syncopal symptoms. He was first diagnosed with HIV in 1985. He was initially started on monotherapy with zidovudine. In 1988, he entered a study for didanosine (ddI) and remained on this monotherapy till 1999. He then received stavudine monotherapy from 1999 until 2001, and then switched to his current therapy of abacavir, lamivudine, and efavirenz. With treatment he has had an undetectable viral load and CD4 count above 400. On presentation he had a Hct drop from 40 to 32. Emergent EGD demonstrated 3 large cords of esophageal varices with stigmata of recent bleeding. Banding ligation was performed with no further bleeding. He had no prior history of liver disease or ETOH abuse. His hepatitis serologies, BMI, LFT's, albumin, PT/INR were all normal. He had a mild thrombocytopenia. Abdominal US demonstrated patent hepatic and portal vasculature, normal appearing liver, and mild splenomegaly with small ascites. Transjugular liver biopsy was performed demonstrating a normal hepatic venous pressure gradient of 4 mmHg. Liver biopsy showed hepatocellular disarray, portal fibrosis, hepatoportal sclersosis with no steatosis, bridging fibrosis or cirrhosis. These findings are consistent with non-cirrhotic portal hypertension likely secondary from his previous prolonged exposure to didanosine. Chronic liver disease in HIV infected patients is increasing in occurrence, often secondary to co-infection with hepatitis B/C, alcohol abuse, fatty liver disease, or medication-induced hepatotoxicity. Non-cirrhotic portal hypertension can be due to portal vein thrombosis, nodular regenerative hyperplasia, incomplete septal cirrhosis, vasculitides, schistosomiasis, or idiopathic (hepatoportal sclerosis). Recent case series and case control studies have shown an association between HIV patients on ART and NCPH. Suspected causes in these patients include medication affect specifically long term ddI therapy versus direct affect from HIV. In HIV patients presenting with upper GI bleed, esophageal varices needs to be considered even in the absence of cirrhosis as NCPH is a potential complication of the ART treatment or HIV itself.

Progression of Fibrosis in HIV and Hepatitis C Virus-Coinfected Patients Treated with Interferon plus Ribavirin-Based Therapy: Analysis of Risk Factors

We determined the prevalence and determinants of worsening fibrosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving anti-HCV therapy. Among 383 HIV-HCV-coinfected patients who received at least 1 dose of anti-HCV treatment (weekly subcutaneous injections of 1.5 mug/kg pegylated interferon-alpha-2b plus daily ribavirin or thrice-weekly subcutaneous injections of 3 MU of interferon-alpha-2b plus daily ribavirin for 48 weeks), paired pretreatment and posttreatment liver biopsy specimens were available and interpretable for 198 cases. Hepatic necroinflammation and fibrosis were graded with Ishak's classification. Histological worsening of fibrosis was defined as a score increase of > or =2 points in patients with fibrosis stage of <4 and as a score increase of 1 point in patients with stage-5 fibrosis. The mean interval +/- standard deviation between the 2 biopsies was 109 +/- 34 weeks. Fibrosis worsened in 34 patients (17.1%). In univariate analysis, ongoing antiretroviral therapy, failure to achieve a sustained viral response, nucleoside reverse-transcriptase inhibitor therapy, didanosine therapy, and stavudine therapy were significantly associated with worsening of fibrosis. Didanosine (odds ratio, 3.34; 95% confidence interval, 1.39-7.96; P = .007) and failure to have a sustained viral response (odds ratio, 9.05; 95% confidence interval, 2.06-39.66; P = .003) remained significantly associated with worsening of fibrosis. The mitochondrial toxicity of antiretrovirals, such as didanosine, seems to play a major role in worsening of fibrosis during HCV therapy. Therefore, anti-HCV therapy should ideally be administered before antiretroviral treatment initiation. If anti-HCV and anti-HIV treatments have to be administered concomitantly, then nucleoside reverse-transcriptase inhibitors with the lowest mitochondrial toxicity should be preferred.

Risk factors and clinical and therapeutic issues of pancreatic abnormalities during HIV infection

of results 166 pts with elevated and/or prolonged laboratory anomalies were focused on to assess pancreatic disease during the cART era. The 435 pts (40.2%) who experienced >1 episode of pancreatic laboratory abnormality had a longer duration of seropositivity and protease inhibitor (PI) exposure, a more frequent immunodeficiency, AIDS diagnosis, chronic liver-biliary disease, and hypertriglyceridemia, while no relation was found with the durationtype of administered nucleoside analogues, when compared with the 646 controls, who never developed pancreatic anomalies. Among the mentioned 435 pts, elevatedprolonged laboratory alterations eventually associated with signs of organ involvement occurred in 166 cases (38.2%), and were related to the administration of ddI, d4T, 3TC, pentamidine, cotrimoxazole, or antimycobacterial therapy, cytotoxic chemotherapy, substance-alcohol abuse, opportunistic infections, chronic liver-biliary disease, a PI-based cART, and hypertriglyceridemia. However, no difference occurred between the 46 pts with clinical-imaging evidence of pancreatic involvement and the remaining 120 asymptomatic pts. Although recurrences of enzyme alterations involved 69.6% of pts, in only 30.1% was a change of the antiretroviral-antimicrobial therapy needed. An acute but uncomplicated pancreatitis occurred in 9/46 symptomatic pts (19.6%). A 2–4week gabexate and/or octreotide administration (performed in 79/166 cases: 47.6%), achieved a significant laboratory, clinical, and imaging cure-improvement in 82.3% of cases, with a better success rate of combined (gabexate+octreotide) vs. single (gabexate or ocreotide) therapy. A significantly reduced tendency to disease recurrences, and a better tolerability of antiretroviral regimens, were also found.

Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

The aim of the study was to investigate the presence of M184I/V in minor HIV-1 populations of patients who failed lamivudine (3TC) and/or didanosine (ddI) treatment. Fourteen 3TC-experienced patients who, after switching therapy to a ddI regimen, had a new failure without M184I/V in the major viral population were included in the study. Ninety plasma samples were analysed by direct sequencing and selective real-time polymerase chain reaction (SPCR), which detects GTG/GTA and ATA mutants down to 1 and 0.2% of the population, respectively. In five samples, SPCR detected resistant virus when direct sequencing detected wild-type M184. In patients with mixed viral populations at sequencing, the median proportion of mutants detected by SPCR was 30%. SPCRGTG reactivity dominated, while SPCRATA reactivity only was uncommon. M184I/V disappeared in patients in whom 3TC was stopped but ddI continued. Ten patients with ddI failure had no M184I/V. Minor HIV-1 strains may harbour M184I/V in patients failing ddI therapy, despite direct sequencing showing wild-type virus. Although M184I/V may reduce the genetic barrier of ddI for mutations such as K65R and L74V, the lack of re-emergence of M184I/V in the minor quasispecies of most patients who failed ddI suggests that M184I/V was not a preferred route to ddI resistance in our patient population.

Low-Level K65R Mutation in HIV-1 Reverse Transcriptase of Treatment-Experienced Patients Exposed to Abacavir or Didanosine

Prior abacavir (ABC) or didanosine (ddI) therapy can result in the L74V/I or K65R mutation in HIV-1 reverse transcriptase. Preexisting K65R may have an impact on the treatment response to tenofovir disoproxil fumarate (TDF). An allele-specific polymerase chain reaction (AS-PCR) assay was developed to detect K65R with a lower limit of quantitation of 0.5%. Among baseline plasma samples from 63 treatment-naive patients, no K65R was detected by AS-PCR. Among baseline samples from 154 treatment-experienced patients, 8 had K65R and 44 had L74V/I by population sequencing. Low-level K65R was detected in an additional 11 patients by AS-PCR, 3 of whom subsequently developed full K65R. Baseline K65R correlated with absence of thymidine analog mutations (TAMs; P = 0.003) and use of ABC or ddI (P = 0.004). Patients with full or low-level K65R at baseline or with L74V/I showed a diminished TDF response. Multivariate analyses confirmed that multiple TAMs, K65R, and L74V/I were independent predictors of diminished TDF response. Prior therapy with ABC or ddI can result in a population genotype that shows K65R or L74V/I but does not reveal low-level K65R present in some patients. Subsequent treatment intensification with TDF resulted in a poor virologic response and may result in expansion of the preexisting K65R mutant.

Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine therapy in HIV infection: a case report and literature review

HIV-infected patients are now treated with combined antiretroviral therapy (CART). Many drugs and/or metabolites are excreted by the kidneys. Furthermore, HIV-infected patients have a high prevalence of preexisting nephropathies, which may or may not be related to HIV [1]. The nucleotide reverse transcriptase inhibitor tenofovir induces tubulopathies and renal insufficiency [2–4]. Nucleoside analogs essentially have mitochondrial toxicity. Nephrotoxicity of these nucleoside analogs is rare. Indeed, didanosine has a good kidney safety profile and only two cases of severe tubular toxicity have been reported [5,6]. Various authors have raised questions about the cumulative nephrotoxicity of didanosine and tenofovir and their respective roles, as their association leads to unexpected side effects in the kidney [7]. Here, we report a case of Fanconi syndrome and nephrogenic diabetes insipidus in an HIV-infected patient receiving a CART regimen including didanosine. We also review the cases that have been published previously, including patients treated with didanosine alone or in combination with tenofovir. We highlight the toxic role of didanosine in this association.

A case–control study of HIV patients with the K65R mutation in the reverse transcriptase gene with virological failure

The K65R mutation in the reverse transcriptase gene can be selected in vitro by tenofovir, as well as by zalcitabine, didanosine and abacavir [1–3]. The importance of this mutation lies in its possible role in multiresistance, which could severely hamper the chances of rescue in HIV patients treated with nucleoside analogues [4–6]. This mutation has also been detected over recent years in patients with early failure who started or simplified a combination treatment regimen with tenofovir as one of the three analogues [7–9]. Although the K65R mutation remains relatively uncommon [10], an increase in its prevalence has been observed over the past few years [11–14]. This trend probably results from the increased use of drugs that select for this mutation, such as tenofovir and didanosine [14]. We determined the incidence and prevalence of the K65R mutation in patients with virological failure and assessed the associated clinical, therapeutic and mutational characteristics, as well as the possibility of rescue. We undertook a genotype study (Trugene HIV-1 genotyping kit; Bayer Healthcare Diagnostics, Tarrytown, New York, USA) as part of a multicentre, 1: 1 case–control study including all patients with virological failure from 12 hospitals in southern Spain. Cases were defined as patients with the K65R mutation after virological failure, and controls consisted of patients matched for age (± 5 years), sex and time of failure (± 4 weeks) who did not have the K65R mutation. The study was undertaken from October 2001 to December 2004. Comparisons of quantitative data between the two groups were assessed using the Mann–Whitney test. Chi-squared statistics were used to test for associations between two qualitative variables, with Yates correction when necessary. All P values are two-tailed. Data were analysed using SPSS statistical software (SPSS Inc., Chicago, Illinois, USA). A total of 2 317 resistance tests were performed in patients whose antiretroviral therapy failed during the study period. The K65R mutation was identified in 64 isolates, representing a prevalence of 2.7%. The rate of the K65R mutation increased over time, from 2.2% in 2001 to 4.3% in 2004. The most common nucleoside reverse transcriptase inhibitors backbone in the antiretroviral regimen was didanosine–tenofovir and the most used drugs were didanosine, tenofovir and abacavir (Table 1). This was the first failure in only 14 cases. All patients except two were rescued with protease inhibitors (PI), with a good response in 72.7% (40/55). Failure with a PI regimen and the presence of thymidine-associated mutations (TAM) were more common in controls, and the use of didanosine, tenofovir and didanosine–tenofovir was more frequent in cases. The CD4 lymphocyte nadir and at failure were lower in cases than in controls. K65R was associated with M184V in 22 cases.Table 1: Patient characteristics with and without the K65R mutation.An increase has occurred in our area over the past few years in the incidence of the K65R mutation in patients with virological failure. The rates are similar to those of other European and American series [10,12,14], except for that of Valer et al. [13], who reported a higher incidence of 10%. As with other series, the mutation was associated with tenofovir and didanosine therapy, especially if they were used with another analogue or non-analogue. The mutation is much less common in association with the failure of PI therapy. The appearance of TAM somehow prevents the appearance of K65R, which reflects the divergent and antagonistic pathways of analogue resistance. Nevertheless, the appearance of this mutation does not imply a worse prognosis and rescue is possible in most patients, perhaps related to the worse viral fitness produced by this mutation, especially in association with M184V [10,15]. In summary, the prevalence of the K65R mutation was low, but its incidence has increased in recent years. The K65R mutation was associated with non-PI regimens and the didanosine–tenofovir combination, and the presence of TAM appears to protect against the K65R mutation. This mutation does not compromise the possibility of rescue.

Once-daily didanosine, lamivudine and nevirapine combination therapy is effective in antiretroviral-naive patients

Once-daily didanosine, lamivudine and nevirapine combination therapy is effective in antiretroviral-naive patients

Fanconi syndrome associated with didanosine therapy

Fanconi syndrome associated with didanosine therapy

Magnitude and Duration of Elevated Gastric pH in Patients Infected with Human Immunodeficiency Virus After Administration of Chewable, Dispersible, Buffered Didanosine Tablets

To test the hypothesis that gastric pH would be elevated above pH 3.0 for at least 2 hours after administration of chewable, dispersible, buffered didanosine tablets. Doses tested were 200 mg (two 100-mg tablets) and 400 mg (two 200-mg tablets). We also sought to compare these doses with regard to maximum gastric pH (pHmax), time to pHmax (TpH-max), time that gastric pH exceeds 3.0 (TpH>3), and area under the gastric pH versus time curve for pH greater than 3.0 (AUCT>pH 3). Prospective, parallel-group, dose-comparison, gastric pH study. General Clinical Research Center, University of Michigan Hospitals, Ann Arbor, Michigan. Nineteen patients infected with human immunodeficiency virus, aged 30-62 years, and receiving long-term didanosine therapy. Patients underwent continuous gastric pH monitoring, using the Heidelberg capsule radiotelemetric pH monitoring device. After documentation of a fasting baseline gastric pH below 3.0, patients were given 180 ml of water (control phase), and gastric pH was allowed to return to baseline. After administration of a single, oral dose of didanosine 200 mg or 400 mg with 180 ml of water, gastric pH was recorded until pH remained below 3.0 for 10 minutes. A mean pHmax of 8.6 (range 6.3-9.5) was achieved with a TpH-max of 4.1 minutes (range 1-12.0 min). Mean TpH>3 was 24.9 minutes (range 15-55 min), with an AUCT>pH 3 of 2.6 pH x min(-1) (range 1.2-6.9 pH x min(-1)). The two doses of didanosine tested did not differ significantly in mean gastric pH parameters. After administration of chewable, dispersible, buffered didanosine tablets, 200 or 400 mg, the mean duration of elevated gastric pH (TpH>3) was less than 30 minutes, with a range of 15-55 minutes. Characterization of the magnitude and duration of elevated gastric pH may allow for earlier administration of other pH-sensitive drugs. The short duration of elevated gastric pH may help explain the wide variability in didanosine bioavailability observed clinically.

Different viral rebound following discontinuation of antiretroviral therapy in cases of infection with viruses carrying L74V or thymidine-associated mutations.

A total of 76 patients discontinued treatment with didanosine plus hydroxyurea after 1 year of maintenance therapy. The greatest human immunodeficiency virus (HIV)-RNA rebounds were seen in 10 patients harboring an L74V mutation, and the presence of viruses with this mutation rapidly waned. In contrast, viral rebounds were significantly less pronounced (P < 0.01) in 12 subjects harboring thymidine-associated mutations; these mutations persisted in all instances. Thus, selection of an L74V mutation during didanosine therapy may compromise HIV replication in vivo.

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.

Mutations conferring resistance to zidovudine diminish the antiviral effect of stavudine plus didanosine

This study evaluated the influence of zidovudine (ZDV) resistance mutations on the antiviral effect of the combination of stavudine (D4T) plus didanosine (ddI) in patients treated previously with ZDV plus zalcitabine (ddC). Twenty patients who had been treated with ZDV plus ddC for a median duration of 11 months (range, 7-42 months) were switched to D4T (40 mg twice a day [BID]) + ddI (200 mg BID) in an open pilot study lasting 6 months. The CDC classes were A (n = 10) and B (n = 10). The median baseline CD4 count was 285/mm(3) and the median baseline plasma virus RNA (Amplicor HIV Monitor RT-PCR assay) was 4.6 log copies/ml. Population-based sequence analysis detected mutations associated with resistance to reverse transcriptase (RT) inhibitors in the RT domain of virus RNA from baseline plasma samples in 13/20 (65%) patients. Twelve patients had mutations associated with zidovudine resistance (3 T215Y - M41L - L210W; 3 T215Y - M41L; 2 T215Y - L210W; 3 T215Y; 1 K70R) and 1 patient had a multi-dideoxynucleoside resistance mutation (QI5IM). Patients with a resistance mutation had a significantly lower RNA suppression after 3 and 6 months (median RNA reduction -0.5 log and -0.1 log) than the remaining patients (-1.6 log and -2 log). Fifty percent of patients with wild-type viruses had undetectable plasma RNA after 24 weeks of D4T plus ddI therapy, whereas all those with mutated viruses had HIV RNA concentration > 3 log copies/ml at week 24 (P <.05). Our finding may have implications when deciding on a second line therapy with three or four drugs that includes two new nucleoside analogues. Cross-resistance between nucleoside analogues deserves maximal attention to ensure optimal antiretroviral therapy and design algorithms for antiretroviral management based on genotypic antiretroviral resistance testing.

Mutations conferring resistance to zidovudine diminish the antiviral effect of stavudine plus didanosine

This study evaluated the influence of zidovudine (ZDV) resistance mutations on the antiviral effect of the combination of stavudine (D4T) plus didanosine (ddI) in patients treated previously with ZDV plus zalcitabine (ddC). Twenty patients who had been treated with ZDV plus ddC for a median duration of 11 months (range, 7–42 months) were switched to D4T (40 mg twice a day [BID]) + ddI (200 mg BID) in an open pilot study lasting 6 months. The CDC classes were A (n = 10) and B (n = 10). The median baseline CD4 count was 285/mm3 and the median baseline plasma virus RNA (Amplicor HIV Monitor RT-PCR assay) was 4.6 log copies/ml. Population-based sequence analysis detected mutations associated with resistance to reverse transcriptase (RT) inhibitors in the RT domain of virus RNA from baseline plasma samples in 13/20 (65%) patients. Twelve patients had mutations associated with zidovudine resistance (3 T215Y - M41L - L210W; 3 T215Y - M41L; 2 T215Y - L210W; 3 T215Y; 1 K70R) and 1 patient had a multi-dideoxynucleoside resistance mutation (QI5IM). Patients with a resistance mutation had a significantly lower RNA suppression after 3 and 6 months (median RNA reduction −0.5 log and −0.1 log) than the remaining patients (−1.6 log and −2 log). Fifty percent of patients with wild-type viruses had undetectable plasma RNA after 24 weeks of D4T plus ddI therapy, whereas all those with mutated viruses had HIV RNA concentration > 3 log copies/ml at week 24 (P < .05). Our finding may have implications when deciding on a second line therapy with three or four drugs that includes two new nucleoside analogues. Cross-resistance between nucleoside analogues deserves maximal attention to ensure optimal antiretroviral therapy and design algorithms for antiretroviral management based on genotypic antiretroviral resistance testing. J. Med. Virol. 59:507–511, 1999. © 1999 Wiley-Liss, Inc.

Meta-analysis of Two Randomized Controlled Trials Comparing Combined Zidovudine and Didanosine Therapy With Combined Zidovudine, Didanosine, and Nevirapine Therapy in Patients With HIV

Meta-analysis of Two Randomized Controlled Trials Comparing Combined Zidovudine and Didanosine Therapy With Combined Zidovudine, Didanosine, and Nevirapine Therapy in Patients With HIV

Meta-analysis of Two Randomized Controlled Trials Comparing Combined Zidovudine and Didanosine Therapy With Combined Zidovudine, Didanosine, and Nevirapine Therapy in Patients With HIV

To extend the range of CD4 counts in which a plasma viral load nadir (pVL) <20 copies/ml was known to be predictive of the duration of virologic response. To determine whether baseline pVL is predictive of virologic response during the study periods. A meta-analysis was conducted of the original individual patient data from two randomized controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP). In total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects on triple therapy with baseline pVL <100,000 copies/ml were more likely to achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml (OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir <20 copies/ml and between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26), respectively, compared with patients with a pVL nadir >400 copies/ml. We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression.

Relation of peripheral neuropathy to HIV treatment in four randomized clinical trials including didanosine

Peripheral neuropathy has been recognized as a dose-limiting adverse effect in Phase I studies of didanosine (ddI) therapy for HIV infection. To study the effect of the currently recommended lower dose of ddI, the databases of 4 randomized, controlled trials were used to assess the frequency of dose-limiting peripheral neuropathy during treatment with ddI 500 or 750 mg/d, compared with zidovudine (ZDV) monotherapy or combination therapy with ddI/ZDV or zalcitabine/ZDV. No between-group differences in risk factors for neuropathy (eg, infectious and metabolic factors, malignancy, concurrent medications) were observed in the individual trials, and the presence of these risk factors appeared to have no increased treatment effect on the occurrence of neuropathy. No significant between-group differences were observed in the individual studies with regard to the incidence or time to onset of peripheral neuropathy. Analysis of the combined results by treatment regimen showed no significant difference in the incidence of neuropathy between recipients of ddI 500 mg/d, ddI 750 mg/d, or ZDV and no significant difference in the cumulative dose received until the onset of neuropathy between the ddI 500- and 750-mg regimens. Entry CD4+ cell counts were significantly predictive of neuropathy, with each 100-cell/μL decrement associated with a 17% increase in risk ( P = 0.002); a CD4+ cell count of <50 cells/μL was highly predictive of neuropathy ( P = 0.0001). In summary, the risk for peripheral neuropathy was not increased by treatment with ddI versus comparator regimens or by treatment with ddI at the dosages used in studies conducted more recently than the Phase I trials. Peripheral neuropathy seems more likely to be associated with advanced HIV infection and lower CD4+ cell counts (particularly counts <50 cells/μL) than with ddI therapy at the currently recommended dose

Didanosine: an updated review of its use in HIV infection.

Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is converted to its active moiety, dideoxyadenosine-5'-triphosphate (ddATP), which inhibits HIV reverse transcriptase and terminates viral DNA growth. It is now well established that didanosine therapy produces beneficial effects on virological and immunological markers of HIV disease and improves clinical outcome in adults or children with HIV infection. In numerous clinical trials, pronounced and sustained decreases in plasma HIV RNA levels and increases in CD4+ cell counts occurred in previously untreated or antiretroviral therapy-experienced patients treated with didanosine in combination with at least 1 other antiretroviral drug; zidovudine, stavudine, lamivudine, nevirapine, nelfinavir and hydroxyurea (hydroxycarbamide) are among the drugs that have been given in combination with didanosine. Of note, HIV RNA levels decreased to below the limits of detection in some patients receiving triple or dual therapy with didanosine-containing regimens. In double-blind, placebo-controlled trials, triple therapy with didanosine, zidovudine and nevirapine was significantly more effective than dual therapy with various combinations of these agents in improving surrogate disease markers in treatment-naive patients and in delaying disease progression or death in treatment-experienced patients with advanced disease. Improvements in virological and immunological markers were greater with didanosine-containing triple regimens than with dual therapy or monotherapy in comparative trials. Triple therapy with didanosine, stavudine and indinavir showed efficacy similar to that of various other triple therapy regimens in nonblind comparative trials. Comparator regimens included combinations of stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and didanosine, stavudine and nevirapine. Combination therapy with didanosine plus hydroxyurea as dual therapy or with a third agent produced marked and sustained decreases in HIV RNA levels in the plasma and in lymph nodes. Combination therapy with didanosine and zidovudine delays disease progression and prolongs survival in patients with intermediate or advanced HIV infection. In large, randomised, double-blind, clinical trials, dual therapy with didanosine plus zidovudine was significantly more effective than zidovudine monotherapy in preventing disease progression and prolonging survival in previously untreated or antiretroviral therapy-experienced patients with intermediate or advanced HIV infection. Pancreatitis and peripheral neuropathy are serious adverse effects of didanosine. These effects are dose-related and usually reversible after discontinuation of treatment. Nausea, vomiting, diarrhoea and/or abdominal pain have been reported in patients receiving treatment with the drug. Didanosine is an effective and generally well tolerated drug in previously untreated and antiretroviral therapy-experienced patients with HIV infection. Given once or twice daily, it has an important role as a component of triple combination regimens for the treatment of patients with symptomatic or asymptomatic HIV infection.