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Lack of Effect from a Previous Single Dose of Nevirapine
on Virologic and Immunologic Responses
After 6 Months of Antiretroviral Regimens Containing
Either Efavirenz or Lopinavir-Ritonavir
Judith N. Dlamini, M.B.B.Ch., Zonghui Hu, Ph.D., Harsha Somaroo, M.B.B.Ch., Helene C. Highbarger, M.S., Dean A. Follmann, Ph.D., Robin L. Dewar, Ph.D., Study Objective. To evaluate the effect of a previous single dose of nevirapine
given to prevent mother-to-child transmission of human immunodeficiencyvirus (HIV) on virologic and immunologic measures after  months of anantiretroviral regimen containing either efavirenz or lopinavir-ritonavir.
Design. Retrospective subgroup analysis of data from the Phidisa II trial.
Setting. Six South African research clinics.
Patients. A total of 394 women with HIV who completed  months of
combination antiretroviral regimen containing either efavirenz or lopinavir-ritonavir as part of the Phidisa II trial.
Measurements and Main Results. During the screening process for the Phidisa II
study, 478 women were asked about previous nevirapine use: 392 women(82%) were nevirapine naïve, and 8 (18%) had received nevirapine. Duringthe study, patients received either an efavirenz-based or lopinavir-ritonavir–based antiretroviral regimen. After  months of treatment, virologic (HIV RNAlevels) and immunologic (CD4+ cell count) responses were measured. Thesedata were compared between women with or without previous nevirapineexposure, and between women who received efavirenz versus lopinavir-ritonavir. After  months of treatment, 394 women (324 nevirapine naïve, 70exposed to nevirapine) had follow-up HIV RNA results. Two hundred twenty-seven (70.1%) of the nevirapine-naïve patients and 48 (8.%) of thenevirapine-exposed patients achieved HIV RNA levels lower than 400 copies/ml(p=0.89), with CD4+ cell count increases of 115.5 and 120.4 cells/mm3,respectively (p=0.7). Among the nevirapine-exposed women, 27 (75%) of 3efavirenz-treated and 21 (1.8%) of 34 lopinavir-ritonavir–treated patients hadHIV RNA levels lower than 400 copies/ml at  months (p=0.31).
Conclusion. In this retrospective analysis of a small cohort, previous exposure
to a single dose of nevirapine did not affect virologic outcomes after months of either an efavirenz-based or lopinavir-ritonavir–based antiretroviralregimen. As efavirenz is one of the first-line combination antiretroviraltherapies administered in Africa, it remains an option for women whoreceived single-dose nevirapine.
Key Words: single-dose nevirapine, efavirenz, human immunodeficiency
virus, HIV, response, antiretroviral, South Africa, women.
(Pharmacotherapy 2011;31(2):158–163)
VIROLOGIC RESPONSE AFTER SINGLE-DOSE NEVIRAPINE Dlamini et al A single dose of nevirapine given during labor had better virologic outcomes after receiving a to pregnant women who are infected with the lopinavir-ritonavir–based antiretroviral regimen human immunodeficiency virus (HIV) and to compared with a nevirapine-based regimen.9 their neonates was a strategy widely used for the However, the difference in these outcomes dimin- prevention of mother-to-child transmission of ished as the time interval increased between HIV-1 infection in resource-limited settings due receiving the single dose of nevirapine and to its efficacy, ease of administration, and low starting the nevirapine-based therapy. Furthermore, cost.1 However, the long half-life of nevirapine a recent study from South Africa suggested that allows for selection of major nonnucleoside exposure to a single dose of nevirapine 18–3 reverse transcriptase inhibitor (NNRTI) resis- months before starting NNRTI-based therapy was tance mutations including K103N, Y181C, and not associated with failure to achieve and sustain G190A that may confer cross-resistance to viral suppression.10 In that study, the presence of the K103N mutation noted before combination commonly used in resource-limited countries.
antiretroviral therapy was started was a strong These mutations may then limit the effectiveness predictor of inadequate treatment response.
of NNRTI-based combination antiretroviral Phidisa II was a randomized, open-label, 2 x 2 therapy used to treat the mother’s HIV infection.2–4 factorial trial conducted at six sites in South In sub-Saharan Africa, NNRTI-based combination Africa to compare the safety and efficacy of antiretroviral therapy remains first-line therapy combination antiretroviral regimens containing as it is less expensive than protease inhibitor– either efavirenz (an NNRTI-based regimen) or based regimens, is available as generic formula- lopinavir-ritonavir (a protease inhibitor) in tions and fixed-dose combinations, and can be patients with advanced HIV disease.11 Using data used in patients coinfected with tuberculosis from this trial, we conducted a retrospective sub- requiring rifamycin-based regimens.5 Protease group analysis to evaluate the effect of a previous inhibitors are reserved for patients who fail or single dose of nevirapine on virologic and cannot tolerate NNRTIs. Several studies, immunologic outcomes after  months of therapy including the Thai Perinatal HIV Prevention Trial with both of these antiretroviral regimens.
27 and the Botswana Mashi Trial,8 however, haveshown less robust virologic outcomes from nevirapine-based antiretroviral regimens at  and12 months in women who had received a single dose of nevirapine during labor, particularly if it accordance with the South African National was received within  months of starting the National Institutes of Health (NIH), and the Recently, the Trial 1 substudy of the Acquired Declaration of Helsinki’s ethical standards on Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) 5208 study (OCTANE) was approved by the SANDF and the NIH–National halted for futility after showing that women Institute of Allergy and Infectious Diseases previously exposed to a single dose of nevirapine institutional review boards. All subjects signedwritten informed consent prior to enrollment.
From Project Phidisa, South African Military Health Key eligibility criteria for Phidisa II included Service, South Africa (Drs. Dlamini and Somaroo); the Division of Clinical Research, National Institute of Allergy and/or family members, age 14 years or older, and Infectious Diseases, National Institutes of Health, current or previous AIDS-defining illness and/or Bethesda, Maryland (Drs. Hu, Follmann, and Pau); and theSAIC-Frederick, Inc., National Cancer Institute, Frederick, CD4+ cell count of less than 200 cells/mm3, and Maryland (Ms. Highbarger and Dr. Dewar).
treatment naïve or fewer than 7 days of antiretro- Funded by the South African Military Health Service, viral drug use. At the patients’ baseline visit, South Africa, and the National Institute of Allergy and demographic information including age, CD4+ Infectious Diseases, National Institutes of Health.
cell count, HIV RNA level, body mass index, Presented at the 1th Conference on Retroviruses and Opportunistic Infections, Montreal, Quebec, Canada, World Health Organization HIV/AIDS stage, and hemoglobin level were collected. In addition, For reprints, visit http://www.atypon-link.com/PPI/loi/phco.
patients were asked about their antiretroviral For questions or comments, contact Alice K. Pau, Pharm.D., drug history. Eligible patients were randomized National Institute of Allergy and Infectious Diseases, to receive either efavirenz or lopinavir-ritonavir, National Institutes of Health, Building 10, Room 11C103,MSC 1880, Bethesda, MD 20892.
with either stavudine plus lamivudine, or PHARMACOTHERAPY Volume 31, Number 2, 2011 Table 1. Baseline Demographic and Clinical Characteristics of the 478 Study Patients
WHO = World Health Organization; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiencysyndrome.
didanosine plus zidovudine, as the nucleoside was also performed to account for any baseline reverse transcriptase inhibitor backbone.
For our retrospective analysis, women who reported nevirapine exposure without exposure to other antiretroviral drugs were assumed tohave received a single dose of nevirapine for Among the 1771 subjects enrolled in Phidisa prevention of mother-to-child HIV transmission; II, 1401 subjects responded to the question of their outcomes were compared with those of the whether they had received nevirapine before women who reported no previous exposure to study enrollment. Four hundred seventy-eight of nevirapine. Specifically, we compared the pro- portion of women who achieved viral suppres- responded that they had received previous nevirapine use. Baseline characteristics of the copies/ml, and the changes in CD4+ cell counts women exposed and not exposed to nevirapine from baseline after  months of combination are shown in Table 1. The women exposed to antiretroviral therapy. Within each patient nevirapine were significantly younger (32.0 vs subgroup (nevirapine exposure and nevirapine 34.7 yrs, p<0.001), had higher hemoglobin levels naïve), we also compared outcomes between (11.88 vs 11.47 g/dl, p=0.031), and had higher those receiving efavirenz-based and those body mass indexes (27. vs 25. kg/m2, p=0.008).
receiving lopinavir-ritonavir–based regimens.
attended a -month follow-up clinic visit.
Seventy (17.8%) had received a single dose of nevirapine—3 were randomized to an efavirenz- Baseline demographic and clinical variables containing regimen and 34 to a lopinavir- were compared between women who received a ritonavir–containing regimen, and 324 women single dose of nevirapine and those who did not (82.2%) had never been exposed to nevirapine— using a two-sample t test for continuous variables 13 each were randomized to the efavirenz and and the Fisher exact test for binary variables.
lopinavir-ritonavir groups. At the -month visit, The Fisher exact test was also used to compare 92.2% of the women were still taking their the virologic suppression rate between these two assigned efavirenz or lopinavir-ritonavir therapy.
A similar proportion of women achieved an HIV efavirenz versus lopinavir-ritonavir in the group RNA level lower than 400 copies/ml in the previously exposed to nevirapine. To account for nevirapine-exposed and nevirapine-naïve groups any baseline imbalances, logistic regression was overall (8.% vs 9.9%, p=0.89 [Table 2]), also used to compare the virologic suppression rate between those who received a single dose of regimen (75.0% vs 74.7%, p>0.99), and among nevirapine and those who did not. A two-sample those receiving an lopinavir-ritonavir–based t test was used to compare the changes in CD4+ regimen (1.8% vs 5.4%, p=0.70). The CD4+ cell counts between the groups; linear regression cell count increases were also similar between the VIROLOGIC RESPONSE AFTER SINGLE-DOSE NEVIRAPINE Dlamini et al Table 2. Virologic and Immunologic Responses at 6 Months
No. (%) of Patients with HIV RNA Levels < 400 copies/ml Patients taking lopinavir-ritonavir–based regimens Mean Increase from Baseline in CD4+ Cell Count (cells/mm3) Patients taking lopinavir-ritonavir–based regimens nevirapine-exposed and nevirapine-naïve groups Phidisa II trial, we found no association between self-reported previous nevirapine use and As Phidisa II was not a randomized trial for the immunologic and virologic outcomes  months comparison between the two subgroups, multi- after starting an efavirenz-based or lopinavir- variate regression was also performed to adjust ritonavir–based antiretroviral regimen. Our for baseline imbalances in age, hemoglobin level, findings are different from the ACTG 5208 trial, and body mass index between the two subgroups.
which found significantly poorer outcomes Multivariate logistic regression indicated no (primary end point defined as death or confirmed significant effect of previous nevirapine use on virologic failure) in women who had received a virologic suppression overall (odds ratio 0.782, single dose of nevirapine at some period before 95% confidence interval 0.433–1.415) or within beginning a nevirapine-containing regimen either the efavirenz or lopinavir-ritonavir groups, compared with a lopinavir-ritonavir–containing and no significant effect of previous nevirapine regimen.9 In the ACTG 5208 trial, the rate of use on CD4+ cell count increases was observed reaching the primary end point declined as the from multivariate linear regression.
duration between receipt of the single dose of Overall, as was seen in the primary Phidisa II nevirapine and the start of nevirapine-based study, significantly more patients randomized to combination antiretroviral therapy increased.
efavirenz achieved HIV RNA levels lower than 400 copies/ml after  months of therapy than efavirenz was used in our study, instead of those randomized to lopinavir-ritonavir (74.7% nevirapine-based combination antiretroviral vs 4.8%, p=0.04).11 A similar pattern was therapy. Although significant cross-resistance observed with those who had received a single exists between efavirenz and nevirapine, for dose of nevirapine (75% vs 1.8%, p=0.31) and patients with susceptible virus, there may be those not exposed to nevirapine (74.7% vs difference in viral responses between the two 5.4%, p=0.09), but these differences were not statistically significant due to the limited sample efavirenz against nevirapine-based combination sizes. For example, in women who had received antiretroviral therapy, showed a trend toward nevirapine (3 randomized to efavirenz and 34 to better virologic outcomes in the efavirenz-treated lopinavir-ritonavir), the power to detect a signifi- subjects than in those who received nevirapine- cant difference of 75% versus 1.8% is only 15%.
based regimens.12 Similar results were reported In addition, no significant difference was noted in Botswana, where virologic failure was seen between the efavirenz and lopinavir-ritonavir groups with regard to CD4+ cell count changes nevirapine-based combination antiretroviral overall (p=0.35), in the women who had received therapy than efavirenz-based therapy.13 There nevirapine (p=0.45), and in those not exposed to could possibly be differences in virologic responses to efavirenz versus nevirapine in thepresence of some NNRTI mutations, which was Discussion
not further investigated in our study. Our data In this retrospective subgroup analysis of the also support the results from other trials PHARMACOTHERAPY Volume 31, Number 2, 2011 comparing efavirenz with lopinavir-ritonavir– received single-dose nevirapine. If available, HIV based regimens, where overall, higher rates of virologic suppression were seen in treatment- detecting early virologic nonresponse or failure naïve subjects treated with efavirenz versus so that a second-line regimen could be started sooner rather than later. With the move to using There are several limitations to our study.
combination antiretroviral therapy instead of First, as this is a post-hoc analysis of a larger single-dose nevirapine for prevention of mother- study, only a small number of patients reported to-child HIV transmission in many countries previous use of nevirapine. The patients were including South Africa, it is hopeful that NNRTI not stratified by previous nevirapine exposure resistance from single-dose nevirapine may previously may differ from nevirapine-naïvewomen in terms of unmeasured characteristics Acknowledgment
that could influence outcome. We used multi- The authors wish to acknowledge the support of the variate linear and logistic regression to correct for Phidisa Executive Committee, the dedication of the measured baseline imbalances. Second, previous site investigators and staff, and the enrollment of the nevirapine use was based on patient recall and not on actual documentation. This was also thecase in other studies in resource-limited coun- References
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