Browsing by Author "Hakim, James"

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    Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa
    (Massachusetts Medical Society., 2014-07-17) Paton, I. Nicholas; Kityo, Cissy; Hoppe, Anne; Reid, Andrew; Kambugu, Andrew; Lugemwa, Abbas; Oosterhout, van J. Joep; Kiconco, Mary; Siika, Abraham; Mwebaze, Raymond; Abwola, Mary; Abongomera, George; Mweemba, Aggrey; Alima, Hillary; Atwongyeire, Dickens; Nyirenda, Rose; Boles, Justine; Thompson, Jennifer; Tumukunde, Dinah; Chidziva, Ennie; Mambule, Ivan; Arribas, R. Jose; Easterbrook, J. Philippa; Hakim, James; Walker, Sarah A.; Mugyenyi, Peter
    Background The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. Methods In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir–ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). Results Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant differ ence in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). Conclusions When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN 37737787, and ClinicalTrials.gov number, NCT00988039.)
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    Neurocognitive Function at the First-Line Failure and on the Second-Line Antiretroviral Therapy in Africa
    (Wolters Kluwer Health, Inc., 2016-04-15) Kambugu, Andrew; Thompson, Jennifer; Hakim, James; Tumukunde, Dinah; van Oosterhout, Joep J.; Mwebaze, Raymond; Hoppe, Anne; Abach, James; Kwobah, Charles
    Objective: To assess neurocognitive function at the first-line antiretroviral therapy failure and change on the second-line therapy. Design: Randomized controlled trial was conducted in 5 sub-Saharan African countries. Methods: Patients failing the first-line therapy according to WHO criteria after .12 months on non-nucleoside reverse transcriptase inhibitors-based regimens were randomized to the second-line therapy (open-label) with lopinavir/ritonavir (400 mg/100 mg twice daily) plus either 2–3 clinician-selected nucleoside reverse transcriptase inhibitors, raltegravir, or as monotherapy after 12-week induction with raltegra vir. Neurocognitive function was tested at baseline, weeks 48 and 96 using color trails tests 1 and 2, and the Grooved Pegboard test. Test results were converted to an average of the 3 individual test z-scores. Results: A total of 1036 patients (90% of those .18 years enrolled at 13 evaluable sites) had valid baseline tests (58% women, median: 38 years, viral load: 65,000 copies per milliliter, CD4 count: 73 cells per cubic millimeter). Mean (SD) baseline z-score was 22.96 (1.74); lower baseline z-scores were independently associated with older age, lower body weight, higher viral load, lower hemoglobin, less education, fewer weekly working hours, previous central nervous system disease, and taking fluconazole (P , 0.05 in multivariable model). Z-score was increased by mean (SE) of +1.23 (0.04) after 96 weeks on the second-line therapy (P , 0.001; n = 915 evaluable), with no evidence of difference between the treatment arms (P = 0.35). Conclusions: Patients in sub-Saharan Africa failing the first-line therapy had low neurocognitive function test scores, but performance improved on the second-line therapy. Regimens with more central nervous system-penetrating drugs did not enhance neurocognitive recovery indicating this need not be a primary consideration in choosing a second-line regimen.