St Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Received 4 April 2004; returned 10 May 2004; revised 15 May 2004; accepted 18 May 2004
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Design and methods: We identified treatment-naive human immunodeficiency virus (HIV-1)-infected individuals who had commenced HAART since 1996 and who had a starting CD4 count of <200 cells/mm3. Immunological success was defined as achieving a CD4 count of >200 cells/mm3 and treatments were compared using univariate and multivariate Cox's proportional hazards models in order to establish whether protease inhibitor (PI)-based regimens were significantly different to regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs). Both regimens utilize a nucleoside analogue (NA) backbone.
Results: A total of 599 patients were identified. When the variables were entered into a multivariate analysis, no significant differences between HAART regimens were found. We showed that compared with efavirenz regimens a two NA plus one PI regimen was not significantly less likely to achieve immunological success (adjusted HR: 0.65, 95% CI 0.411.03, P=0.07). Two NA and boosted PI (adjusted HR: 1.33, 95% CI 0.81 to 2.16) or two NA and nevirapine (adjusted HR: 0.93, 95% CI 0.671.29) regimens were also not significantly different from efavirenz-based regimens, based on the endpoint of immunological success.
Conclusion: PI-, boosted PI- and NNRTI-based HAART regimens are not significantly different in achieving increased CD4 counts in individuals who commence therapy with a low CD4 count.
Keywords: HAART , immune , PI , NNRTI , boosted
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
However, approximately one-third of all patients in the developed world commence HAART with a CD4 count of <200 cells/mm3.1113 It is essential that these individuals achieve virological suppression and immune recovery as quickly as possible in order to minimize the risk of AIDS-defining OIs. A number of studies have shown that a good virological and immunological response to HAART can be achieved regardless of the CD4 count at initiation of therapy1416 and though some studies have shown a plateau in CD4 response after 2 years of HAART8,17,18 there are data to suggest that suppression of viraemia and maintenance of CD4 counts continues through year 5 of therapy in patients who achieve ongoing viral suppression.19,20
While studies have compared different HAART regimens in treatment-naive individuals,14,2023 there are no prospective comparative data regarding the optimal choice in patients starting treatment with a low CD4 count. Using prospectively collected data from a single centre, we have compared the immunological response to different HAART regimens in patients commencing therapy with a CD4 count of <200 cells/mm3.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Using this database we identified all treatment-naive patients commencing HAART, defined according to consensus guidelines as triple therapy consisting of nucleoside analogue backbone and non-nucleoside reverse transcriptase inhibitors (NNRTIs) and/or protease inhibitors (PIs).9,10 HAART was commenced routinely at this institution on 1 January 1996 and all patients commencing treatment with a CD4 count exceeding 200 cells/mm3 were excluded. Immunological success was defined as achieving a CD4 count of >200 cells/mm3. Data were extracted for this study on 1 August 2003.
Quantitative data were categorized into quartiles and these were stratified by individuals who achieved immunological success during first-line HAART. Event time was defined as time from commencing HAART to either achieving CD4 cell count >200 cells/mm3, switch from first-line therapy or time of death if it occurred while on first-line therapy; data were otherwise censored on the day of extraction. Time to immunological success was estimated using the KaplanMeier product limit survival method. Between-group comparisons of different HAART combinations were assessed using log rank 2 test. These were further investigated using univariate and multivariate Cox's proportional hazards regression analysis to identify these and other factors predicting the likelihood of immunological success.
Variables found to be significant (P< 0.2) in a univariate analysis were used to build a multivariate model, as described previously.24,25 Since antiretroviral prescriptions have changed over time during the HAART era, the final multivariate model was stratified by year of starting therapy and baseline CD4 cell count, respectively, to match and minimize residual bias due to these factors. Baseline CD4 count was also stratified into quartiles according to Cox's proportional hazards model. The multivariate model was tested for its distributional assumptions using the CoxSnell residual plot. All P values presented are two-tailed and all data analyses were performed in SAS statistical software, version 8.0.
CD4 subset analysis was performed routinely using whole blood stained with murine anti-human monoclonal antibodies to CD4 (TetraOne, Beckman Coulter, High Wycombe, UK) and were evaluated on an Epics XL-MCL (Beckman Coulter) flow cytometer.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Most of the 599 individuals (62.1%) commenced NNRTI-based HAART (34.4% of these started on nevirapine, 65.6% on efavirenz), 31.7% started on a single PI-based regimen and 6.2% on a ritonavir-boosted PI; all included a nucleoside analogue backbone. Of the single PI-based regimens, 37% received indinavir, 28% nelfinavir, 26% saquinavir hard gel and 9% saquinavir soft gel.
Table 1 shows the results of a univariate analysis. This demonstrated that age, baseline CD4 and first-line HAART regimen but not baseline viral load were significantly associated with immunological success. Overall, 63.1% of patients starting an efavirenz-based regimen achieved a CD4 count of >200 cells/mm3, and the rates for nevirapine, boosted PI and unboosted PI were 60.6%, 52.2% and 45.9%, respectively. Unboosted PI-based regimens performed significantly worse than efavirenz in the univariate analysis.
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
While limitations to this study included the absence of randomization and the likelihood that patients with a low CD4 count were more frequent attenders, these data suggest that effective HAART across its recognized classes, is suitable to increase the CD4 count to >200 cells/mm3, in those individuals who commence HAART with a low CD4 count. Censoring of the database was performed at the first switch of therapy as despite the reason for switching (including compliance issues, toxicity, resistance or lack of potency), a lack of immunological response as manifest by a falling CD4 count would have been observed until appropriate re-institution of an alternative therapy.
Comparative studies have suggested previously that there may be superior efficacy of ritonavir-boosted PI-based regimens when compared with unboosted PIs.22,2527 Inferiority of unboosted PI-based regimens compared with efavirenz is consistent with the results of other studies though these have generally studied patients with higher starting CD4 counts. Our results would suggest that the same is true in a more severely immunosuppressed population. Study 006 showed significantly better viral suppression at 48 weeks for efavirenz compared with indinavir (both with zidovudine/lamivudine) and similar CD4 cell rises (mean CD4 at entry was 350 cells/mm3).14 In ACTG384, efavirenz was virologically superior to nelfinavir when combined with a zidovudine/lamivudine backbone with similar CD4 changes.28 Efa VIP-2 compared efavirenz with unboosted PI-based regimens (mostly indinavir and nelfinavir) in patients with CD4 counts of <100 cells/mm3 (median 37).29
Efa VIP-2 also showed significantly greater discontinuations in patients receiving PI-based as opposed to efavirenz-based HAART for both adverse events and virological failure, though the discontinuation rate in the PI group may, at least partly, have been influenced by the greater proportion in that group receiving a didanosine/stavudine backbone. CD4 cell count increases were also greater in individuals on efavirenz-based regimens with significantly greater CD4 cell count at 24 months with a significantly higher rate of achievement of a CD4 cell count rise of >100 and >200 cells/mm3).29
Our present study also suggests that nevirapine performs no better with respect to immunological parameters as compared with unboosted PIs. The Atlantic study compared nevirapine, indinavir or lamivudine with a stavudine/didanosine backbone in patients with a CD4 count of >200 cells/mm3 and although there was no significant difference in success between the nevirapine- and indinavir-based regimens, there was a non-significant trend towards a smaller CD4 count increase in nevirapine-treated patients, similar to the situation observed here.30 Nevirapine has also been shown to achieve similar virological success rates when compared with nelfinavir, with a trend favouring nevirapine at 12 months.31
Bartlett et al.32 performed a review of HAART trials published between July 1994 and February 2000 in treatment-naive patients. The median CD4 count in these 23 trials was 375 cells/mm3 (range 185473), i.e. higher than in our cohort; a comparison within this study between two nucleoside analogues (NA) and PI/NNRTI/3rd NA revealed similar viral suppression and CD4 increases in the three groups at 48 weeks. Neither baseline CD4 nor viral load were significant predictors of viral suppression and once again, while sub-group analysis suggested a better response to efavirenz compared with nevirapine, this was not statistically significant. Our results show similar immunological outcomes for efavirenz and nevirapine.
Prior to the landmark 2NN trial, which compared first-line therapy containing either nevirapine, efavirenz or both in addition to stavudine and lamivudine,33 efavirenz had consistently outperformed nevirapine in a number of cohort studies.3439 However, the 2NN trial showed no significant difference between efavirenz and nevirapine with respect to virological suppression at 48 weeks, even in patients with a low CD4 cell count at initiation of therapy. It has been argued that the study was underpowered and therefore failed to rule out the inferiority of nevirapine rather than showing the two drugs to be equivalent. A recent sub-group analysis within the 2NN randomized cohort of individuals commencing therapy at CD4 cell counts of <200 cells/mm3 showed that efavirenz performed significantly better virologically at CD4 counts of <25 cells/mm3 but that there was no significant difference between the efavirenz- and nevirapine-based regimens in the CD4 cell count range 25200 cells/mm3 with respect to viral suppression. Efavirenz and nevirapine have been shown previously to be equally effective but the numbers in this study were small (<30 patients in each arm).40
Efavirenz has been shown to be highly efficacious regardless of initial CD4 count41,42 and these data support this. While we have not compared the response rates to nevirapine for different starting CD4 counts, our data do reveal similar success rates for both the NNRTIs, suggesting a good response to nevirapine at low CD4 counts.
We were unable to demonstrate a significant difference between HAART regimens in this group of patients, using a prospective database. There was a trend towards poorer CD4 response to unboosted PI-based regimens but these no longer constitute a reasonable choice for first-line therapy. The trend for a superior response to boosted PI- as opposed to NNRTI-based regimens may warrant further studies comparing ritonavir-boosted PIs with NNRTIs in individuals with low CD4 cell counts.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2
.
Hammer, S. M. (2002). Increasing choices for HIV therapy. New England Journal of Medicine 346, 20223.
3
.
Stebbing, J., Gazzard, B. & Douek, D. C. (2004). Where does HIV live? New England Journal of Medicine 350, 187280.
4
.
Ho, D. D. (1995). Time to hit HIV, early and hard. New England Journal of Medicine 333, 4501.
5 . Markowitz, M., Vesanen, M., Tenner-Racz, K. et al. (1999). The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. Journal of Infectious Diseases 179, 52737.[CrossRef][ISI][Medline]
6
.
Gottlieb, M. S. (2001). AIDSpast and future. New England Journal of Medicine 344, 178891.
7
.
Ahdieh-Grant, L., Yamashita, T. E., Phair, J. P. et al. (2003). When to initiate highly active antiretroviral therapy: a cohort approach. American Journal of Epidemiology 157, 73846.
8 . Detels, R., Tarwater, P., Phair, J. P. et al. (2001). Effectiveness of potent antiretroviral therapies on the incidence of opportunistic infections before and after AIDS diagnosis. AIDS 15, 34755.[CrossRef][ISI][Medline]
9
.
Yeni, P. G., Hammer, S. M., Carpenter, C. C. et al. (2002). Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS SocietyUSA Panel. Journal of the American Medical Association 288, 22235.
10 . Pozniak, A., Gazzard, B., Anderson, J. et al. (2003). British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Medicine 4, Suppl 1, 141.[CrossRef]
11 . Lee, R. & Monteiro, E. F. (2003). Third regional audit of antiretroviral prescribing in HIV patients. International Journal of STD and AIDS 14, 5860.[CrossRef][Medline]
12 . Curtis, H., Sabin, C. A. & Johnson, M. A. (2003). Findings from the first national clinical audit of treatment for people with HIV. HIV Medicine 4, 117.[CrossRef][Medline]
13 . Sabin, C. A., Lampe, F. C., Chaloner, C. et al. (2003). An audit of antiretroviral treatment use in HIV-infected patients in a London clinic: the limitations of observational databases when auditing antiretroviral treatment use. HIV Medicine 4, 8793.[CrossRef][Medline]
14
.
Staszewski, S., Morales-Ramirez, J., Tashima, K. T. et al. (1999). Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. New England Journal of Medicine 341, 186573.
15 . Staszewski, S., Miller, V., Sabin, C. et al. (1999). Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy. AIDS 13, 9516.[CrossRef][ISI][Medline]
16 . Opravil, M., Ledergerber, B., Furrer, H. et al. (2002). Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count > 350 x 106/l. AIDS 16, 137181.[CrossRef][ISI][Medline]
17 . Notermans, D. W., Pakker, N. G., Hamann, D. et al. (1999). Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults. Journal of Infectious Diseases 180, 10506.[CrossRef][ISI][Medline]
18 . Tarwater, P. M., Margolick, J. B., Jin, J. et al. (2001). Increase and plateau of CD4 T-cell counts in the 3(1/2) years after initiation of potent antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 27, 16875.[ISI][Medline]
19 . Hunt, P. W., Deeks, S. G., Rodriguez, B. et al. (2003). Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 17, 190715.[CrossRef][ISI][Medline]
20 . Egger, M., May, M., Chene, G. et al. (2002). Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 360, 11929.[CrossRef][ISI][Medline]
21 . Delta Coordinating Committee. (1996). Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 348, 28391.[CrossRef][ISI][Medline]
22
.
Autran, B., Carcelain, G., Li, T. S. et al. (1997). Positive effects of combined antiretroviral therapy on CD4 + T cell homeostasis and function in advanced HIV disease. Science 277, 1126.
23
.
Walmsley, S., Bernstein, B., King, M. et al. (2002). Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. New England Journal of Medicine 346, 203946.
24 . Portsmouth, S., Stebbing, J., Gill, J. et al. (2003). A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS 17, 1722.[CrossRef]
25 . Stebbing, J., Portsmouth, S., Nelson, M. et al. (2004). The efficacy of ritonavir in the prevention of AIDS-related Kaposi's sarcoma. International Journal of Cancer 108, 6313.[CrossRef][ISI]
26 . Montaner, J. S. G., Saag, M. S., Barylski, C. et al. (2002). FOCUS study: saquinavir qd regimen versus efavirenz qd regimen 48 week analysis in HIV infected patients. In Program and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, 2002, San Diego, USA. Abstract H-167, p. 261. American Society for Microbiology, Washington, DC, USA.
27
.
Pati, S., Pelser, C. B., Dufraine, J. et al. (2002). Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 99, 37719.
28 . Robbins, G. (2002). Antiretroviral strategies in naive HIV + subjects: comparison of sequential 3-drug regimens (ACTG384). In Fourteenth International AIDS Conference, Barcelona, Spain, Abstract LbOr20B.
29 . Pulido, F., Arribas, J. & Miro, J. M. (2002). Comparative study of efavirenz or protease inhibitor-based HAART in HIV-infected, antiretroviral naive patients with <100 CD4 cells/mL and opportunistic disease (EFA VIP-2 study). In Fourteenth International AIDS Conference, Barcelona, Spain. Abstract TuOrB1187, p.372. International AIDS Society, Stockholm, Sweden.
30 . Lange, J. M. (2003). Efficacy and durability of nevirapine in antiretroviral drug naive patients. Journal of Acquired Immune Deficiency Syndromes 34, Suppl 1, S40S52.[Medline]
31 . Podzamczer, D., Ferrer, E., Consiglio, E. et al. (2002). A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antiviral Therapy 7, 8190.[ISI][Medline]
32 . Bartlett, J. A., DeMasi, R., Quinn, J. et al. (2001). Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS 15, 136977.[CrossRef][ISI][Medline]
33 . Van Leth, F., Hassink, E., Phanuphak, P. et al. (2003). Results of the 2NN study: a randomised comparative open label trial of first line antiretroviral therapy with regimens containing either nevirapine, efavirenz or both drugs combined, in addition to stavudine and lamivudine. In Abstracts of the Tenth International Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, Abstract 176.
34 . Keiser, P., Nassar, N., Yazdani, B., Armas, L. & Moreno, S. (2003). Comparison of efficacy of efavirenz and nevirapine: lessons learned for cohort analysis in light of the 2NN study. HIV Clinical Trials 4, 35860.[ISI][Medline]
35 . Fumaz, C. R., Tuldra, A., Ferrer, M. J. et al. (2002). Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens. Journal of Acquired Immune Deficiency Syndromes 29, 24453.[ISI][Medline]
36 . Haas, D. W., Fessel, W. J., Delapenha, R. A. et al. (2002). Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial. Journal of Infectious Diseases 183, 392400.[CrossRef][ISI]
37 . Keiser, P., Nassar, N., White, C. et al. (2002). Comparison of nevirapine- and efavirenz-containing antiretroviral regimens in antiretroviral-naive patients: a cohort study. HIV Clinical Trials 3, 296303.[Medline]
38 . Cozzi-Lepri, A., Phillips, A. N., d'Arminio Monforte, A. et al. (2002). Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) study. Journal of Infectious Diseases 185, 10629.[CrossRef][ISI][Medline]
39 . Matthews, G. V., Sabin, C. A., Mandalia, S. et al. (2002). Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. AIDS 16, 5361.[CrossRef][ISI][Medline]
40 . Nunez, M., Soriano, V., Martin-Carbonero, L. et al. (2002). SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clinical Trials 3, 18694.[Medline]
41 . Van Leth, F., Andrews, S., Grinsztjen, B. et al. (2004). Virologic failure in antiretroviral therapy naive patients is only determined by extreme low values of CD4 + cells or high values of HIV-1 RNA concentration, not by choice of treatment with nevirapine or efavirenz. In Abstracts of the Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, USA. Abstract 550.
42 . Staszewski, S., Gallant, J., Pozniak, A., et al. (2003). Efficacy and safety of tenofovir df versus stavudine when used in combination with lamivudine and efavirenz in antiretroviral naive patients: 96 week preliminary interim results. In Abstracts of the Tenth International Conference on Retroviruses and Opportunistic Infections, Boston, USA, Poster 564b.