Marianne Harris

The nephrotoxic effects of HAART

With significant reductions in mortality and risk of progression to AIDS in the era of highly active antiretroviral therapy (HAART), complications of long-standing HIV infection and treatment have become increasingly important. Such complications include the nephrotoxic effects of HAART, which are the subject of this Review. The most common nephrotoxic effects associated with HAART include crystal-induced obstruction secondary to use of protease inhibitors (mainly indinavir and atazanavir), and proximal tubule damage related to the nucleotide analog reverse transcriptase inhibitor tenofovir. Acute kidney injury (AKI) can occur following tenofovir-induced tubule dysfunction or as a result of severe mitochondrial dysfunction and lactic acidosis induced by nucleoside reverse transcriptase inhibitors. The potential insidious long-term renal toxicity of antiretroviral treatment is probably underappreciated in patients with HIV: a proportion of patients with treatment-related AKI did not recover their baseline renal function at 2-year follow-up, suggesting the possibility of permanent renal damage. Finally, nonspecific metabolic complications might increase the risk of vascular chronic kidney disease in patients on HAART. However, given the benefits of HAART, fear of nephrotoxic effects is never a valid reason to withhold antiretroviral therapy. Identification of patients with pre-existing chronic kidney disease, who are at increased risk of renal damage, enables appropriate dose modification, close monitoring, and avoidance or cautious use of potentially nephrotoxic medications.

A comparison of the predictive performance of different methods of kidney function estimation in a well-characterized HIV-infected population.

Background: Glomerular filtration rate (GFR) estimation equations have never been validated in the HIV population. This pilot study aimed to compare all currently available methods of kidney function assessment with nuclear GFR in HIV-infected adults. Methods: Patients underwent GFR measurement with 99mTc-diethylenetriaminepentaacetic acid (Tc-99m Pentetate), and measured values were compared with results of creatinine-based estimation equations [abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) formula and Cockcroft-Gault (CG) formulae], 24-hour urine creatinine clearance and estimated cystatin C GFR. Results: Twenty-seven HIV-infected adults were studied. Most were male and Caucasian, with a mean age of 52 years. Median CD4 was 290 cells/mm3, 70% of patients had HIV RNA <50 copies/ml and all were receiving highly active antiretroviral therapy (median 5 drugs). Median Tc-99m Pentetate-GFR was 91 ml/min/1.73 m2. Despite greater bias and similar accuracy, the MDRD formula was more precise than the CG formula, regardless of whether CG estimations were corrected for ideal body weight or body surface area. Relative accuracy within 30% of nuclear GFR was greater for the MDRD formula than for all other methods. The performance of 24-hour urine creatinine clearance was similar to that of the MDRD formula for patients with GFR <90 ml/min/1.73 m2, although it performed less well at higher GFR. The performance of cystatin C GFR was inferior to that of all the creatinine-based methods. Conclusions: While no method of kidney function estimation performed highly, both 24-hour urine creatinine clearance and the MDRD formula performed with a level of precision and accuracy sufficient for clinical decision making. Our findings support the preferential use of the MDRD formula in the treated HIV population and suggest that there are no HIV-specific factors that limit equation applicability. Larger validation studies are needed to confirm our findings and allow generalization to the HIV population at large.

The Steady-State Pharmacokinetics of Efavirenz and Nevirapine When Used in Combination in Human Immunodeficiency Virus Type 1–Infected Persons

The steady-state pharmacokinetics of efavirenz and nevirapine, when used in combination to treat human immunodeficiency virus type 1 (HIV-1)-infected subjects, were investigated. HIV-1-infected persons who had used efavirenz (600 mg once daily) for > or =2 weeks were eligible for study inclusion. The plasma pharmacokinetics of efavirenz were determined over 24 h. Subsequently, nevirapine (400 mg once daily) was added to the regimen. After 4 weeks, the pharmacokinetics of efavirenz and nevirapine were assessed over 24 h. The differences between the pharmacokinetic parameters of efavirenz with and without nevirapine were analyzed, and the pharmacokinetics of nevirapine were compared with those in historical control patients. The exposure to efavirenz when combined with nevirapine was significantly decreased by 22% (area under the plasma concentration vs. time curve), 36% (minimum plasma concentration), and 17% (maximum plasma concentration). Nevirapine pharmacokinetics appear to be unaffected by coadministration of efavirenz, compared with data from historical control patients.

Clinical uses of non-nucleoside reverse transcriptase inhibitors.

Three non‐nucleoside reverse transcriptase inhibitors (NNRTIs) are currently available for treatment of HIV‐1 as part of combination antiretroviral therapy. Oral dosing is administered three times daily for delavirdine (DLV), twice daily for nevirapine (NVP), and once daily for efavirenz (EFV). Rash is a common side effect of all three NNRTIs, and early CNS side effects are also frequent with EFV. Hepatotoxicity is relatively uncommon but requires appropriate monitoring. Drug interactions mediated by the cytochrome P450 system are an important consideration when the NNRTIs are administered concomitantly with other drugs, including protease inhibitors (PIs). HIV strains with reduced susceptibility to NNRTIs can occur with a single mutation in the reverse transcriptase (RT) gene. The available NNRTIs exhibit overlapping genotypic resistance patterns, but newer agents may overcome this problem. NNRTIs have been studied in combination with nucleoside RT inhibitors for first‐line HIV therapy, where they have shown at least equivalent antiviral efficacy compared with PI‐based regimens over 1–2 years of therapy. NVP and EFV have also been studied as a replacement for a PI within a virologically successful regimen, with the aim of preventing or reducing PI toxicities and simplifying the dosing regimen. Such ‘switch’ strategies are successful for certain patients in maintaining virologic suppression for 6 months or more and result in varying degrees of improvement in PI‐associated toxicities. NNRTIs may offer a benefit when included in salvage regimens for patients failing PI‐based therapy, particularly in patients who have not previously been treated with NNRTIs. NVP has been shown to have a substantial favourable impact on the rate of vertical HIV‐1 transmission with a simple, cost‐effective regimen. Copyright

Case series assessing the safety of mycophenolate as part of multidrug rescue treatment regimens

Abstract BACKGROUND: Mycophenolate mofetil (MMF), an inhibitor of lymphocyte proliferation, is emerging as a potential adjunct in the treatment of HIV-1 infection. By potentiating the activity of abacavir, MMF may improve antiviral efficacy. However, it may also lead to myelosuppression, such as was seen in patients taking hydroxyurea-containing regimens. PURPOSE: To assess the safety of MMF as adjunctive therapy for HIV infection. METHOD: Eighteen HIV-positive outpatients, given MMF (500 mg po bid) on a compassionate basis as part of their salvage therapy, were monitored for adverse effects. RESULTS: Five patients discontinued MMF between 26-68 days of follow-up due to adverse effects likely related to other factors. Among the remaining 13 patients, no new clinically significant cytopenias occurred over 107-154 days of follow-up. Three patients exhibited decreases in CD4 counts, despite decreases in plasma HIV-1 RNA. CONCLUSION: Short-term follow-up suggests that MMF (500 mg po bid) does not cause lymphocyte suppression. However, further studies are ongoing to determine its safety and efficacy profile in HIV infection.

Improved Survival in HIV-Associated Diffuse Large B-Cell Lymphoma with the Addition of Rituximab to Chemotherapy in Patients Receiving Highly Active Antiretroviral Therapy

Abstract Purpose: Recent trials suggest serious toxicity in HIV-associated non-Hodgkin’s lymphoma (NHL) with rituximab (R) and chemotherapy (CT), offsetting the benefit of rituximab. Method: We retrospectively reviewed experience with CHOP-R vs. CT in 40 patients with HIV-associated diffuse large B-cell lymphoma (DLBCL) diagnosed between December 1992 and February 2006, all of whom were treated with curative intent. Results: In a univariate analysis, International Prognostic Index (IPI) score, prior AIDS, HAART, and rituximab were significant for overall survival (OS). In a multivariate analysis, IPI 0-1 (p < .02), no prior AIDS (p < .0002), and receiving CHOP-R (p < .01) were significant for improved OS, and HAART use (p < .09) retained a trend for improved OS. The hazard ratio (HR) for patients with high IPI receiving CHOP-R was 0.3 (95% CI 0.1-0.8). Patients without prior AIDS receiving CHOP-R had an HR of 0.5 (95% CI 0.1-1.7). The OS at 30 months in patients not receiving HAART was 0%. With HAART, OS was 33% for CT and 86% for CHOP-R; HR for CHOP-R was 0.4 (95% CI 0.1-1.2). Toxic deaths were 3 (33%) for CHOP-R and 6 (25%) for CT (p = ns); all toxic deaths with CHOP-R were in patients not receiving HAART. Rituximab-treated patients had a lower death rate from lymphoma (CHOP-R, 2 [16%] vs. CT, 15 [63%]; p < .04), and overall mortality (CHOP-R, 5 [42%] vs. CT, 21 [88%]; p < .01). Conclusion: These retrospective data suggest that fatal toxicity of rituximab in HIV-NHL is not increased provided HAART is used, that the addition of rituximab to CT improved outcome, and that further prospective trials investigating this issue are warranted.

Regimen-dependent variations in adherence to therapy and virological suppression in patients initiating protease inhibitor-based highly active antiretroviral therapy.

To examine differences among four protease inhibitor (PI)‐based drug regimens in adherence to therapy and rate of achievement of virological suppression in a cohort of antiretroviral‐naive patients initiating highly active antiretroviral therapy (HAART).

Use of metabolic drugs and fish oil in HIV-positive patients with metabolic complications and associations with dyslipidaemia and treatment targets.

Highly active antiretroviral therapy (HAART) with protease inhibitors (PI) is successful in suppressing viral replication, but may lead to a range of metabolic abnormalities associated with cardiovascular disease (CVD).

A large prospective study assessing injection site reactions, quality of life and preference in patients using the Biojector® vs standard needles for enfuvirtide administration*

To determine the severity of injection site reactions (ISRs), patient quality of life (QoL) and preference when enfuvirtide is administered by the Biojector® (Bioject, Medical Technologies, Inc., Tualatin, OR, USA) relative to standard needles.

Rapid rebound in hepatitis B DNA in previously undetectable hepatitis B/HIV co-infected patients switching from tenofovir to entecavir therapy

of results Six patients switched from tenofovir to entecavir in 2007. All patients were male with a median age of 49 yrs (IQR 46–58 yrs) and a median CD4 count of 500 cells/mm3 (IQR 253–658 cells/mm3). All patients were hepatitis Be antigen positive, and had undetectable HBV viral loads while on tenofovir therapy prior to initiation of entecavir. 5/6 patients had prior HBV DNA samples available for genotypic testing; 100% revealed evidence of baseline lamivudine resistance (presence of L180 M + M204 V) but no evidence of entecavir-associated resistance mutations. Patients were treated with entecavir 1 mg daily or renallyadjusted equivalent. Lamivudine was maintained within the antiretroviral regimen of 5/6 patients. All patients experienced HBV rebound on entecavir. Median time to HBV virologic rebound was 2 months (range 1–11 months), and the median HBV DNA viral load at rebound was 226,012 copies/mL (IQR 6,771–492,237 copies/mL). Only one patient experienced a rise in ALT (to 143 IU/mL) at the time of initial HBV rebound. All patients maintained HIV virologic suppression during the substitution period and at the time of HBV rebound.