Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir

The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination.     

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.     

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.     

Amprenavir and didanosine are associated with declining kidney function among patients receiving tenofovir

OBJECTIVE: To examine the effect of antiretroviral agents and clinical factors on the development of tenofovir-associated kidney dysfunction. METHODS: Observational cohort study of HIV-infected patients receiving tenofovir in an HIV clinic population. Patients' kidney function prior to initiating and while receiving tenofovir was evaluated in relation to other antiretroviral medications and demographic and clinical characteristics. Decline in kidney function was assessed by the glomerular filtration rate (GFR) as estimated by the Cockcroft-Gault (CG) equation, which incorporates weight. Logistic regression analysis was used to examine factors associated with GFR of > 90, 60-90, 30-60, and < 30 ml/min per 1.73 m(2) while on tenofovir. Secondary analyses used the simplified Modification of Diet in Renal Disease (MDRD) equation. RESULTS: Among the 445 patients initiating tenofovir, 51 (11%) developed a decline in kidney function. In multivariate analysis, there was a significant association between decline in kidney function and concurrent use of amprenavir [odds ratio (OR) 3.6; P = 0.045] and didanosine (OR, 3.1; P = 0.006), age over 50 years (OR, 4.4; P = 0.03), and lower baseline weight (OR, 0.95/kg; P < 0.001). Patients identified with kidney dysfunction by the MDRD equation did not fully overlap with those identified by the CG equation. CONCLUSIONS: Didanosine and amprenavir use, increased age, and lower baseline weight were significantly associated with risk for kidney dysfunction among patients receiving tenofovir. GFR results using the MDRD equation were inconsistent with those using CG, which highlights the impact of including weight in the estimation of GFR among HIV-infected patients.     

Severe toxicity associated with the combination of tenofovir and didanosine: case report and review

The combination of tenofovir and didanosine results in an increase in the didanosine plasma exposure and might augment the risk for didanosine toxicity. Although pharmacokinetic studies support a didanosine dose reduction to 250 mg when used concurrently with tenofovir in patients weighing at least 60 kg, no data are available in lower-weight patients. We describe a case of lactic acidosis and acute liver failure in a low-weight patient receiving tenofovir and a reduced dose of didanosine (200 mg/day). To our knowledge, this is the first case of severe toxicity associated with a reduced dose schedule of didanosine. Previous cases of severe toxicity associated with the combination of tenofovir and didanosine are reviewed.     

High rate of virological failure in maintenance antiretroviral therapy with didanosine and tenofovir

We evaluated the virological outcome of tenofovir plus didanosine-based regimens in 67 HIV-suppressed patients. After a median follow-up of 26 months (IQR 10.5-40.5), 12 (18%) discontinued the therapy because of virological failure. At virological failure 'de novo' selected mutations were identified in 11 of the 12 failing patients, including the K65R mutation in seven patients. These results argue against the use of tenofovir-didanosine not only in naive patients, but also in previously suppressed patients.     

Impact of a treatment including tenofovir plus didanosine on the selection of the 65R mutation in highly drug-experienced HIV-infected patients

Data from 20 highly drug-experienced HIV-infected patients receiving tenofovir plus didanosine as part of a salvage regimen were analysed. At baseline, all but one patient harboured a virus bearing at least one nucleoside excision mutation (NEM); in 13 cases (65%) three or more NEM were detectable. After a median of 26 weeks of treatment, two patients (10%) selected the 65R mutation. These results support the hypothesis that NEM hinder the selection of this mutation.     

Renal dysfunction and tenofovir toxicity in HIV-infected patients

Potentially nephrotoxic drugs are only 1 of several causes of renal dysfunction in HIV. Data from the period before the wide use of tenofovir show a variety of prerenal, renal, and obstructive causes of acute renal failure (ARF) in HIV outpatients. Results of clinical trials of tenofovir indicate a rate of ARF of approximately 1%, with observational cohort data indicating a somewhat higher rate. Thus, in evaluating patients with rising serum creatinine levels, including those receiving tenofovir, diagnostic efforts should go beyond discontinuation of potentially offending drugs. This article summarizes a presentation on renal dysfunction in HIV and renal toxicity of antiretroviral drugs made by Lynda A. Szczech, MD, MSCE, at an International AIDS Society-USA Continuing Medical Education course in Washington, DC, in May 2008. The original presentation is available as a Webcast at www.iasusa.org.     

A randomized, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naive, HIV-infected Thai patients

OBJECTIVES: To evaluate the safety and efficacy of four different regimens of didanosine (ddI) + stavudine (d4T) in HIV-infected Thais. DESIGN: Prospective, open-label, randomized study. METHODS: Patients were randomized to four regimens of high and low doses of ddI and d4T or to ddI alone. D4T was added to the ddI-alone arm after week 24. The duration of study was 48 weeks. RESULTS: Seventy-eight patients were randomized (mean CD4 cell count, 255 x 10(6)/l; mean plasma HIV-1 RNA; 4.3 log10 copies/ml). In the intent-to-treat analysis, 78% of patients in the pooled combination arms and 20% of the patients in the ddI alone arm (to which d4T was added after 24 weeks) showed plasma HIV-1 RNA < 500 copies/ml at week 24 (P < 0.001), and 59% versus 53% at week 48, respectively. In addition, the proportion of patients with < 50 HIV-1 RNA copies/ml was 13% versus 7% at week 24 (P = 0.5) and 17% versus 20% at week 48 respectively. At week 24, median CD4 cell count increases from baseline were 101 x 10(6)/l in the pooled combination versus 76 x 10(6)/l in the ddI alone arm (P = 0.78). Logistic regression modeling suggested a correlation between receiving high dose ddI and achieving HIV-1 RNA < 500 copies/ml at week 48 (P = 0.07). CONCLUSIONS: The d4T/ddI combination was superior to ddI alone in producing HIV-1 viral suppression. At week 48, > 60% of patients treated with this combination reached HIV-1 RNA levels < 500 copies/ml. Receiving high dose ddI but not d4T may correlate with a better viral suppression.     

Hepatitis C virus infection is associated with painful symptoms in HIV-infected adults

The study aim was to assess whether hepatitis C virus (HCV) was associated with painful symptoms among patients with HIV. Using data from a prospective cohort of HIV-infected adults with alcohol problems, we assessed the effects of HCV on pain that interfered with daily living and painful symptoms (muscle/joint pain, headache and peripheral neuropathy). Exploratory analyses assessed whether depressive symptoms and inflammatory cytokines mediated the relationship between HCV and pain. HCV-infected participants (n = 200) had higher odds of pain that interfered with daily living over time (adjusted odds ratio [AOR] 1.43; 95% CI: 1.02-2.01; p = 0.04) compared to those not infected with HCV. HIV/HCV co-infected participants had higher odds of muscle or joint pain (AOR 1.45; 95% CI: 1.06-1.97; p = 0.02) and headache (AOR 1.57; 95% CI: 1.18-2.07; p<0.01). The association between HCV and peripheral neuropathy did not reach statistical significance (AOR 1.33; 95% CI: 0.96-1.85; p = 0.09). Depressive symptoms and inflammatory cytokines did not appear to mediate the relationship between HCV and pain. Adults with HIV who are also co-infected with HCV are more likely to experience pain that interfered with daily living, muscle or joint pain, and headaches compared to those not co-infected. Research is needed to explore the association between HCV infection and pain, and to determine whether HCV treatment is an effective intervention.