In a recent review of triple combination therapy trials among treatment-naive HIV patients updated from their earlier meta-analysis, Bartlett and colleagues [1,2] found superior viral suppression in antiretroviral therapy (ART) regimens containing non-nucleoside reverse transcriptase inhibitors (NNRTI) and boosted protease inhibitors (PI). Convenient dosing, lower pill burdens, better tolerance, and PI-sparing have made NNRTI-based regimens pivotal in ART initiation. NNRTI efficacy for treatment-naive HIV patients has been assessed during clinical trials [1–4] lasting 24 weeks for drug approval from the US Food and Drug Administration, and data on fewer patients remaining on their treatment arms are available to 96 weeks. Lipid profile differences have been shown for patients treated with NNRTI compared with PI . Little is known about the long-term clinical outcomes despite reports of NNRTI use in clinical practice [6,7]. We assessed not only the effectiveness of NNRTI-based initial ART in clinical practice, but also the development of coronary artery disease, diabetes mellitus and hyperlipidemia in treatment-naive HIV patients.
A retrospective review of treatment-naive patients assessed changes in the CD4 cell count, HIV-RNA level, lipid profiles, the development of HIV genotypic mutations and co-morbidities such as coronary artery disease, diabetes mellitus, and hyperlipidemia during NNRTI-based initial ART without PI during 1998–2004. Hypertension served as a control prevalent co-morbidity. Continuous and categorical variables were analysed by Student's t-test and by Fisher's exact test, respectively.
Forty-nine patients without the four exclusionary co-morbidities started NNRTI-based ART. Their median age was 44 years (range 30–64), 98% were men, and 82% were African-American. The total follow-up for all patients was 1420 patient-months. Nineteen patients had pre-ART clinical events or opportunistic infections. All patients initiated ART with two or more nucleoside/nucleotide reverse transcriptase inhibitors (NRTI; such as didanosine, lamivudine, stavudine, tenofovir, and zidovudine) and a single NNRTI (40 efavirenz and nine nevirapine). Two individuals changed from efavirenz to nevirapine because of disturbing dreams and depression on efavirenz. None received concomitant didanosine and tenofovir.
Table 1 summarizes laboratory data before and on therapy. Among 21 patients with baseline CD4 cell counts of less than 200 cells/μl, 76% achieved CD4 cell counts greater than 200 cells/μl on NNRTI. CD4 cell increases were sustained, and no patient developed any adverse events of immune reconstitution. Complete viral suppression was achieved in 87% of patients tested at a median of 125.5 days after baseline. These CD4 cell counts and viral responses exceeded earlier reports [1–4,6,7].
Among 40 patients with undetectable viremia, 75% sustained complete viral suppression for a median of 728 days (range 28–2071), and 25% failed with circulating median HIV RNA of 2825 copies/ml (range 82–53 698) after median treatment of 23 months (range 6–49). K103N was the only mutation detected in three patients. As NNRTI have a low genetic resistance barrier , our results contrast with an earlier report in which NNRTI resistance-associated mutations were not detected among treatment-naive patients, but were found in 10 out of 12 patients exposed to previous suboptimal ART despite greater than 95% adherence during their virological rebound .
The median time on NNRTI for our patients was 27 months (range 0.8–71), and 21 patients (43%) continued therapy beyond the 6-year observation. The reasons for stopping NNRTI for 28 patients included four virological failures, seven drug-related adverse effects (anemia, diarrhea, nausea, fatigue, zidovudine-related myopathy and trimethoprim–sulfamethoxazole-related rash), 15 non-adherence, and two moved. Among the non-adherent patients, 13 out of 15 had achieved undetectable viremia on therapy. Our results confirm successful viral suppression for the majority of patients despite 31% non-adherence as reported previously .
More patients achieved high-density lipoprotein (HDL) of 40 mg/dl or greater compared with baseline (31/39 versus 15/31, P = 0.0107). A difference between baseline and NNRTI treatment was shown for the total cholesterol: HDL ratio (0.7 with 95% confidence interval 0.2–1.3), and the lipid changes in Table 1 suggest a less atherogenic profile on NNRTI therapy . A reversal of these lipid changes was observed before or at the time of detectable viremia for a few patients with virological failure, implying that those patients were not fully adherent to ART, or viral replication may have a direct effect on lipid profiles . In contrast to published reports [11–13], no lipid differences were observed between nevirapine compared with efavirenz treatment.
For clinical outcomes, two patients (4%) developed hyperlipidemia 8 and 11 months after starting NNRTI-based ART. No patients had documented diabetes mellitus or coronary artery disease on NNRTI. One patient (2%) developed hypertension (control co-morbidity) 19 months after starting nevirapine-based therapy. No AIDS-defining events or deaths occurred.
In clinical practice, NNRTI-based initial ART was durable and effective for CD4 cell response, viral suppression, and lipid profile improvement despite suboptimal adherence. Hyperlipidemia developed in 4% of patients compared with hypertension (control) in 2%; none developed diabetes or coronary artery disease. All patients survived with no clinical progression.
The views expressed in this article are those of the author and do not necessarily reflect the policies of the Department of Veterans Affairs.
1. Bartlett JA, Fath MJ, DeMasi R, Hermes A, Quinn J, Mondou E, Rousseau F. An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS 2006; 20:2051–2064.
2. Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1-infected adults. AIDS 2001; 15:1369–1377.
3. Lange JM. Efficacy and durability of nevirapine in antiretroviral drug naive patients. J Acquir Immune Defic Syndr 2003; 34(Suppl. 1):S40–S52.
4. Van Leth F, Andrews S, Grinsztejn B, Wilkins E, Lazanas MK, Lange JMA, et al
. The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART. AIDS 2005; 19:463–471.
5. Van der Valk M, Kastelein JJP, Murphy RL, van Leth F, Katlama C, Horban A, et al
. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001; 15:2407–2414.
6. Corales RB, Shrestha NK, Taege AJ, Isada C, Rehms, Schmitt S, et al
. Protease-sparing regimen in a real-life practice with naive patients: an equal opportunity approach? HIV Clin Trials
7. Manfredi R, Calza L, Chiodo F. Efavirenz versus nevirapine in current clinical practice: A prospective, open-label observational study. J Acquir Immune Defic Syndr 2004; 35:492–502.
8. Johnson VA, Brun-Vezinet F, Clotet B, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD. Update of the drug resistance mutations in HIV-1: fall 2006. Top HIV Med 2006; 14:125–130.
9. De la Rosa R, Ruiz-Mateos E, Rubio A, Abad MA, Vallejo A, Rivero L, et al
. Long-term virological outcome and resistance mutations at virological rebound in HIV-infected adults on protease inhibitor-sparing highly active antiretroviral therapy. J Antimicrob Chemother 2004; 53:95–101.
10. Maggiolo F, Ravasio L, Ripamonti D, Gregis G, Quinzan G, Arici C, et al
. Similar adherence rates favor different virologic outcomes for patients treated with nonnucleoside analogues or protease inhibitors. Clin Infect Dis 2005; 40:158–163.
11. Van Leth F, Phanuphak P, Stroes E, Gazzard B, Cahn P, Raffi F, et al
. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med 2004; 1:e19.
12. Fontas E, van Leth F, Sabin CA, Friis-Moller N, Rickenbach M, d'Arminio Monforte A, et al
. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis 2004; 189:1056–1074.
13. El-Sadr WM, Mullin CM, Carr A, Gibert C, Rappoport C, Visnegarwala F, et al
. Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort. HIV Med 2005; 6:114–121.