Treatment of HIV‐infected patients with a combination of efavirenz, nevirapine and nucleoside reverse transcriptase inhibitors

Recently, the results of the 2NN study have been reported [1]. This study was an open-label, randomized, comparative trial of first-line antiretroviral therapy with regimens based on stavudine (d4T) plus lamivudine (3TC) plus either efavirenz (EFV), nevirapine (NVP) or both nonnucleoside reverse transcriptase inhibitors (NNRTIs) taken simultaneously (the 2NN group), with a dose adjustment of 800 mg of EFV dosed with 400 mg NVP once a day (qd). There was no statistically significant difference reported between the results for EFV and NVP, but the 2NN group showed lower treatment efficacy because of increased adverse events. On the basis of these results, use of NVP plus EFV is not recommended. In this context, we report the findings of a pilot study conducted to investigate both the tolerance and the efficacy of NVP and EFV in combination with nucleoside reverse transcriptase inhibitors (NRTIs), either in protease inhibitor (PI)-sparing regimens or as a second-line therapy in patients with failing PI-based regimens. Thirty consecutive patients without previous experience of NNRTIs were enrolled prospectively and divided into two groups: group 1 consisted of treatment-naïve patients and patients who had undergone previous treatments that included PIs and who had viral loads <50 copies/mL for at least 6 months, and group 2 consisted of patients with failing PI-based regimens. All patients were treated with NVP, EFV and didanosine (ddI) in a triple regimen, with the exception of nine patients with previous experience or adverse effects with ddI, for whom this drug was substituted by zidovudine (ZDV)/d4T plus 3TC, in a quadruple regimen. The dose of NVP was the usual 200 mg qd for 15 days followed by 200 mg twice a day (bid) indefinitely, but the dose of EFV was increased to 800 mg qd because of pharmacological interference between NVP and EFV, according to data of Veldkamp et al. [2]. EFV was added after the patients had taken NVP for 1 month. The doses of the other drugs were those commonly used: ddI, 250 or 400 mg qd adjusted to body weight; ZDV, 250 mg bid; d4T, 30 or 40 mg bid adjusted to body weight, and 3TC, 150 mg bid. All patients were reevaluated at 3 and 6 months by clinical assessment and determination of viral load (VL), CD4, and biochemical and haematological parameters. Statistical analysis was performed using the χ2 and Fisher's exact tests to compare proportions, and the t-test and Mann–Whitney test to compare continuous variables. Patients that did not complete the follow-up period because of secondary adverse effects were not included in the analysis. Severe adverse events were considered grades III and IV according to the World Health Organization (WHO) classification. Clinical hepatitis was defined as symptoms of liver disease associated with an elevation of >3-fold normal levels of transaminases. Appropriate informed consent was obtained, and the guidelines for human experimentation of our institution were followed in conducting the clinical research. Of the 30 patients, 21 were male and nine female, with a mean (±SD) age of 38±7 years. Twenty patients had coinfection with the hepatitis C virus, but none had portal hypertension. There were 19 patients in group 1, of whom three were treatment-naïve and 16 had previously undergone successful HAART with PI regimens. There were 11 patients in group 2. All the patients on treatment in group 1 had less than 50 HIV-1 RNA copies/mL at 6 months follow-up. In group 2, six of eight patients on treatment did not achieve undetectable levels of HIV or had early rebound (P= 0.002). The increase in CD4 count was also superior in group 1 to group 2 (P=0.06). Nine patients (30%) had severe adverse effects, six in group 1 and three in group 2 (P=1): two patients developed clinical hepatitis (defined as symptoms of liver disease associated with an elevation of >5-fold normal levels of transaminases); two had central nervous system disturbances; two showed gastric intolerance, and three had a severe skin rash. The two cases of clinical hepatitis occurred within the first 12 weeks of therapy and showed values of transaminases >5-fold the normal range. Values of transaminases and clinical symptoms returned to normal once antiretroviral drugs were discontinued. The cases of rash appeared when the patients were taking the complete regimen, between the 4th and 8th weeks. In this study, all patients who completed the follow-up period and who had no history of previous failing regimens (group 1) treated with a combination of NVP, EFV and ddI (or ZDV/d4T plus 3TC) had viral loads of <50 copies/mL at 6 months, whereas six of eight patients with previous failing PI-based regimens (group 2) did not achieve undetectable levels of HIV after treatment with this regimen. The increase in CD4 count was also superior in group 1 to group 2. Because NVP and EFV have the same target and similar genetic resistance barriers [3, 4], they probably act as double therapy when they are combined with only one NRTI. This could at least partially explain why the effect was better in group 1 than in group 2. In relation to toxicity, 30% of the patients had severe adverse effects that led to treatment interruption. This percentage is higher than that reported with regimens of treatment that include only one NNRTI and very similar to the 2NN study results, where the proportion of patients who came off their randomized NNRTI during the course of the study was 20% with EFV, 22% with NVP twice daily, 29.1% with NVP once daily, and 34.5% in the 2NN group [1]. Particularly worrying is hepatic toxicity. In our study, two patients had clinical hepatitis, i.e. a percentage (6.3%) higher than reported in others works, with a similar proportion of hepatitis C virus coinfection. The two cases occurred within the first 12 weeks of therapy, and transaminase values and clinical symptoms returned to normal once antiretroviral drugs were discontinued, so it is very unlikely that they were attributable solely to hepatitis C virus infection. Although the number of patients in this study was small and it was a noncomparative study, the results suggest that a regimen including NVP and EFV together is associated with a higher incidence of adverse effects, principally clinical hepatitis.