Most HIV-positive women and children exposed to nevirapine (Viramune) during the peripartum period can go on to use the drug when they need highly active antiretroviral therapy (HAART) for their own health, researchers reported.
But a significant minority will not respond to nevirapine-based treatment, even if they do not have resistance to the drug, according to two reports in the Oct. 14 issue of the New England Journal of Medicine.
Single-dose nevirapine is widely used to help prevent mother-to-child transmission of HIV and is also a mainstay of combination treatment in places where medical resources are limited. But early exposure to the drug, even for a short period of time, has been shown to select for resistance mutations and it has not been clear how that affects future treatment options.
"This poses an important public health challenge," argued Marc Lallemant, MD, and Gonzague Jourdain, MD, both of the Harvard School of Public Health.
In an editorial in the same issue of the journal, they noted that nevirapine-based treatments are the most widely available and affordable in the developing world, where the vast majority -- some 95% -- of infections of children and infants take place.
The two studies, taken together, confirm expectations that exposure to nevirapine would lead to a diminished response in later treatment, they wrote, and support recent World Health Organization recommendations to use another regimen in such cases.
In six African countries, researchers led by Paul Palumbo, MD, of Dartmouth Medical School, examined the issue in 164 children ages 6 months to 3 years who had been exposed to nevirapine. The patients were treated with a combination of zidovudine and lamivudine (Combivir) plus either nevirapine or ritonavir-boosted lopinavir (Kaletra).
The primary endpoint of the study was virologic failure or discontinuation of the study drug. The study was stopped early, after a recommendation by its data safety monitoring committee, but a parallel trial, in children not exposed to nevirapine at birth, is continuing.
Meanwhile, researchers led by Shahin Lockman, MD, of Brigham and Women's Hospital in Boston, studied 745 women eligible for triple-drug therapy, including 241 previously exposed to nevirapine. In concurrent parallel trials, they were treated with a combination of tenofovir and emtricitabine (Truvada) plus either nevirapine or lopinavir-ritonavir.
The primary endpoint was virologic failure or death.
In the children's study, dubbed P1060, 56% of the patients had stage 3 or 4 disease, according to WHO categories; the median percentage of CD4-positive T cells was 19%.
All told, 39.6% of children in the nevirapine group reached the primary endpoint, the researchers reported, compared with 21.7% in the lopinavir-ritonavir arm. The weighted difference was 18.6 percentage points and was significant at P=0.02.
Baseline resistance to nevirapine was detected in 18 of 148 children (or 12% of those tested) and predicted treatment failure. Specifically:
- 83.3% of those with resistance in the nevirapine group failed therapy compared with 18.2% in the lopinavir-ritonavir group.
- In contrast, among the 130 children without resistance, the proportions were 35.8% and 20.3%, respectively.
The results can be seen as "lending urgency" to the WHO recommendations that a protease inhibitor-based regimen should be used among those previously exposed to nevirapine, Palumbo and colleagues argued.
The adult study, whose details were first reported last year, had similar results.
Among the women previously exposed to nevirapine, Lockman and colleagues reported, 26% in the nevirapine group reached the primary endpoint, compared with 8% in the ritonavir-boosted lopinavir group, a difference that was significant at P=0.001.
Virologic failure occurred in 28 women in the nevirapine group versus nine in the ritonavir-boosted lopinavir group, the researchers reported. Also, four women in the nevirapine group died without prior virologic failure, compared with one in the ritonavir-boosted lopinavir group).
In contrast, Lockman and colleagues reported, among the women not previously exposed to the drug, 34 of 249 women in the nevirapine group and 36 of 251 in the ritonavir-boosted lopinavir group either had virologic failure or died -- 14% in each arm.
As with the children, baseline resistance to nevirapine predicted treatment failure. Only 14% of women exposed to the drug had resistance, but 73% of them in the nevirapine group reached a primary endpoint, compared with 6% in the ritonavir-boosted lopinavir group. The difference was significant at P=0.006.
Among the women who did not show baseline nevirapine resistance, 19% of those in the nevirapine group and 9% of those in the ritonavir-boosted lopinavir group reached a primary endpoint (P=0.04).
The adult study was supported by the National Institute of Allergy and Infectious Diseases, the National Center for Research, and the NIH. Study drugs were provided by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, and GlaxoSmithKline.
Lockman reported no conflicts, but several authors reported financial links with a range of pharmaceutical companies and others are employed by the industry.
The study in children was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health. Boehringer Ingelheim Pharmaceuticals, Abbott Laboratories, and GlaxoSmithKline supplied study drugs.
Palumbo reported no conflicts.
Lallemant reported no conflicts.
Jourdain reported owning stock or stock options in sanofi-aventis.
- Reviewed by Barry S Zingman, MD; Professor of Clinical Medicine, Albert Einstein College of Medicine, Bronx, NY and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
New England Journal of MedicineSource Reference: Lockman S, et al "Antiretroviral therapies in women after single-dose nevirapine exposure" N Engl J Med 2010; 363: 1499-1509.
New England Journal of MedicineSource Reference: Palumbo P, et al "Antiretroviral treatment for children with peripartum nevirapine exposure" N Engl J Med 2010; 363: 1510-1520.
New England Journal of MedicineSource Reference: Lallemant M, Jourdain G "Preventing mother-to-child transmission of HIV - protecting this generation and the next" N Engl J Med 363; 16: 1570-1573.