To the Editor:
A recent report in the journal reported the extent of immune recovery seen with different combinations of highly active antiretroviral therapy (HAART). 1 A total of 1083 drug-naive patients started a protease inhibitor (PI) regimen while 439 initiated a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based combination. Nevirapine (NVP) was used by 94% of subjects in the latest group. The authors concluded that significantly higher CD4+ lymphocyte increases occurred at 24 months in the group receiving NNRTI-containing regimens in comparison with the PI-treated group. We think that several aspects of the study may be misleading.
The study seems to have been done in the same group of drug-naive patients in whom the immune response to PI-based regimens was already reported in 2002. 2 At that time, the authors suggested that attenuated immune recoveries in patients receiving PI-based combinations could be attributable to the relatively high frequency of episodes of intermittent viremia and insufficient drug compliance in those patients. In fact, only half of individuals who initiated a PI-based combination were optimally compliant and showed persistently undetectable viremia, which translated into greater CD4+ cell gains. In the rest, lower treatment compliance resulted in low-level viremia, despite which CD4 gains occurred although they were more modest. Given those findings, it is unfortunate that in their most recent report, in which Wood et al. 1 compared CD4 gains in patients taking PI- and NNRTI-based regimens, the authors did not adjust for plasma HIV RNA response in their multivariate analysis. The assessment of CD4 recovery, rather than having been performed on an-intent-to-treat basis, should have better been done considering patients remaining on their initial treatment arm (PI or NNRTI, respectively).
There are several differences between NNRTIs and PIs that merit particular attention. While PIs may show higher genetic barrier for resistance than NNRTIs, side effects tend to be more frequent with PIs than with NNRTIs, 3 particularly for the older PIs (indinavir, ritonavir, saquinavir, and nelfinavir) assessed in analysis by Wood et al. In contrast, side effects leading to drug discontinuation often are fewer and concentrated within the first weeks of therapy with NNRTI. Furthermore, the low genetic barrier for resistance of NNRTI (and of NVP in particular) means that poor treatment compliance may rapidly translate into virologic failure with high-level resistance, which requires changes in treatment to be made without delay. This was demonstrated in one study in which subjects on NNRTIs (NVP in 75%) with adherence <95% showed an 8-fold higher risk of virologic failure than perfectly compliant patients. 4 Of note, NNRTI resistance mutations at viral rebound were recognized in up to 83% of failures. In contrast, poor drug compliance in patients taking PI-based regimens is often associated with episodes of transient viremia or with persistent low-level viremia. In this situation, PI-resistant mutations accumulate very slowly, and treatment changes are more often deferred. 5
In summary, the characteristic safety profile and the relative greater robustness of PIs over NNRTIs for selecting drug resistance may facilitate blipping of viremia or low-level viremia more often in patients receiving PIs than NNRTIs. This aspect is critical and was ignored in the analysis of Wood et al., 1 in which patients who initiated PIs were compared with others who begun NNRTIs. Most likely, the former experienced more blips or low-level viremia than the latter. A recent study has underscored that patients with frequent HIV RNA determinations <1000 copies/mL show a lower CD4+ T-cell recovery than those with sustained complete viral suppression or just a few episodes of blipping viremia. 6
When CD4 gains are assessed in patients who initiate PI- vs. NNRTI-based regimens, taking into account viral load responses during the follow-up, the results are fairly different. For example, Dronda et al. 7 showed that the rate of immunologic failure was less frequent in subjects attaining complete virus suppression with their first HAART regimen, taking PI in respect to using NNRTI (relative risk, 0.16; 95% CI, 0.06–0.42). In the APACHE database, which includes 3753 HIV-positive subjects who initiated PI (82%) or NNRTI (8%) regimens, the chances of experiencing small CD4+ cell gains were significantly higher in patients receiving NNRTIs when compared with those on PIs (relative risk, 1.9; 95% CI, 1.3–2.7), despite a similar interval to achieve undetectable viremia in both treatment modalities. 8 Finally, in the ATHENA cohort, the average slope rise of CD4+ cells in patients receiving nelfinavir or NVP regimens, after adjusting for viral load response at week 12, was significantly better in subjects who started with the former. 9
In a case-control observational study, we assessed the CD4 gain in drug-naive patients who initiated PIs vs. NNRTIs (NVP in 80%). Only patients who achieved undetectable viral load at week 12 and remained aviremic throughout the following 36 weeks were selected. The mean increase in CD4+ cells tended to be greater in the PI arm in comparison with the NNRTI arm (+260 cells/μL vs. +221 cells/μL, P = NS). However, the CD4 gain was significantly more pronounced taking PIs than NNRTIs in the subgroup of patients who begun HAART with <300 CD4+ cells/μL. In them, the CD4 gain was +277 cells/μL with PIs and +155 cells/μL with NNRTIs. 10
The retrospective nature of the aforementioned studies is an important limitation of all of them. The Atlantic study is an international and randomized prospective trial in which 3 treatment modalities were compared in drug-naive subjects. 11 The virologic outcome at 96 weeks yielded superior results with NVP over indinavir-based combinations, reflecting a better compliance with the former regimen. However, the CD4 gain adjusted for baseline CD4+ cell counts and time on effective treatment was significantly better in patients receiving indinavir in comparison with those on NVP (+238 cells/μL and +139 cells/μL on average, respectively).
A look to other prior studies points in the same direction in different settings. For instance, the CD4 gain in the INCAS trial, 12 in which NVP plus 2 nucleosides were administered to drug-naive subjects, was of 139 cells/μL at 48 weeks, which is in agreement with what was seen in the Atlantic trial. Moreover, in a meta-analysis of 9 randomized trials of treatment simplification in patients under PI regimens with undetectable viremia, a trend towards better immune recovery was noticed for subjects who continued on PIs vs. those who switched to PI-sparing regimens, despite very poor virologic outcomes in the former group. 13
Several mechanisms have been proposed to explain this apparent greater immunologic benefit of PIs over NNRTIs. Testing patients with undetectable viremia using more sensitive HIV RNA tests, we firstly noticed a deeper suppression of HIV replication in patients receiving PIs over NNRTIs (NVP in almost all instances). 14 Similarly, other studies conducted thereafter demonstrated a stronger virus suppression in the lymphoid tissue in patients undergoing PI with respect to those on NVP, despite sustained undetectable plasma viremia with both treatment modalities. 15,16 Altogether, these studies suggest that PI-based regimens may show stronger and broader antiviral activity than combinations that only include RTIs.
Conversely, it has been suggested that the extent of immune recovery seen with PIs may go beyond their pure antiviral inhibitory effect. In pediatrics, Ye et al 17 recently showed a more efficient reconstitution of peripheral blood recent thymic emigrant CD4+ T cells when using PI-based regimens. A specific effect of PIs on thymic cells could explain this finding. Furthermore, PIs may interfere with programmed cell death phenomena of CD4+ T lymphocytes, a phenomenon that is not seen with other anti-HIV drugs. 18 Finally, deleterious immune activation phenomena, which result in further loss of CD4+ cells in HIV infection, may be alleviated by PIs. 19
In light of these findings, we think that PIs may provide a faster and higher CD4 recovery than PI-sparing regimens, including those based on NNRTIs, when the analyses are done adjusting for complete viral load suppression. This consideration is particularly of value for the selection of initial HAART regimens in patients presenting with severe immunodeficiency, in whom immune recovery should be the first priority. Thereafter, when CD4 counts have increased enough, concerns about treatment compliance and toxicity issues may move the convenience of the chosen HAART regimen to the forefront of consideration. Then, NNRTIs may show some advantages over most of the current PIs.
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17. Ye P, Kourtis A, Kirschner D. Reconstitution of thymic function in HIV-1 patients treated with highly active antiretroviral therapy. Clin Immunol
18. Phenix B, Angel J, Mandy F, et al. Decreased HIV-associated T cell apoptosis by HIV protease inhibitors. AIDS Res Hum Retroviruses
19. Benito JM, Lopez M, Martin JC, et al. Differences in cellular activation and apoptosis in HIV-infected patients receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors. AIDS Res Hum Retroviruses