Neurocognitive Function at the First-Line Failure and on the Second-Line Antiretroviral Therapy in Africa: Analyses From the EARNEST Trial.

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 raltegravir. 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 -2.96 (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

The virological durability of first-line ART among HIV-positive adult patients in resource limited settings without virological monitoring: a retrospective analysis of DART trial data.

BACKGROUND: Few low-income countries have virological monitoring widely available. We estimated the virological durability of first-line antiretroviral therapy (ART) after five years of follow-up among adult Ugandan and Zimbabwean patients in the DART study, in which virological assays were conducted retrospectively. METHODS: DART compared clinically driven monitoring with/without routine CD4 measurement. Annual plasma viral load was measured on 1,762 patients. Analytical weights were calculated based on the inverse probability of sampling. Time to virological failure, defined as the first viral load measurement ≥200 copies/mL after 48 weeks of ART, was analysed using Kaplan-Meier plots and Cox regression models. RESULTS: Overall, 65% of DART trial patients were female. Patients initiated first-line ART at a median (interquartile range; IQR) age of 37 (32-42) and with a median CD4 cell count of 86 (32-140). After 240 weeks of ART, patients initiating dual-class nucleoside reverse-transcriptase inhibitor (NRTI) -non-nucleoside reverse-transcriptase (NNRTI) regimens containing nevirapine + zidovudine + lamivudine had a lower incidence of virological failure than patients on triple-NRTI regimens containing tenofovir + zidovudine + lamivudine (21% vs 40%; hazard ratio (HR) =0.48, 95% CI:0.38-0.62; p < 0.0001). In multivariate analyses, female patients (HR = 0.79, 95% CI: 0.65-0.95; p = 0.02), older patients (HR = 0.73 per 10 years, 95% CI: 0.64-0.84; p < 0.0001) and patients with a higher pre-ART CD4 cell count (HR = 0.64 per 100 cells/mm3, 95% CI: 0.54-0.75; p < 0.0001) had a lower incidence of virological failure after adjusting for adherence to ART. No difference in failure rate between the two randomised monitoring strategies was observed (p= 0.25). CONCLUSIONS: The long-term durability of virological suppression on dual-class NRTI-NNRTI first-line ART without virological monitoring is remarkable and is enabled by high-quality clinical management and a consistent drug supply. To achieve higher rates of virological suppression viral-load-informed differentiated care may be required. TRIAL REGISTRATION: Prospectively registered on 18/10/2000 as ISRCTN13968779

Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

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 difference 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, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.)

Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial

Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial

Characteristics for all enrolled infants and according to whether they had received no or ≥90% in utero exposure to tenofovir.

<p><i>p</i>-Values from Wilcoxon rank sum tests (continuous) or chi-squared tests (categorical).</p>a<p>Excludes <i>n = </i>9 with 22%–89% in utero exposure to tenofovir from comparison.</p>b<p>One regimen with abacavir, one with nevirapine, and 11 with tenofovir.</p>c<p>Lopinavir/ritonavir plus lamivudine/tenofovir/nevirapine (one), didanosine/nevirapine (one), didanosine/abacavir (two).</p>d<p>Five switched to second line 9–21 wk into pregnancy (one of whom also had multiple substitutions on first and second line due to hypersensitivity and wrong dispensing); five had first-line substitutions (efavirenz to nevirapine [one] and stavudine to zidovudine [three] plus lamivudine/tenofovir; stavudine to lopinavir/ritonavir [for lipoatrophy]); four had second-line substitutions from efavirenz to nevirapine (two with lamivudine/lopinavir/ritonavir, two didanosine/lopinavir/ritonavir); and two intensified boosted protease inhibitor monotherapy (one with zidovudine/lamivudine/tenofovir for 33 wk, one with nevirapine for 15 wk of the pregnancy).</p>e<p>Nevirapine single dose + zidovudine no length given (one), nevirapine only 1 wk (seven), nevirapine 1 wk + zidovudine 1 wk (one), zidovudine only 2–4 wk (four), zidovudine single dose (one), zidovudine and lamivudine 1 wk (three), didanosine 1 wk (one), stavudine 1 week (one).</p>f<p>Closest within 9 wk before (<i>n = </i>76; median 20 d; IQR 12–30) or after (<i>n = </i>94; median 25 d; IQR 14–35) delivery for 170/176 pregnancies.</p>g<p>176 pregnancies in 152 mothers: median (IQR) pre-ART CD4 per mother 100 (34–145); <i>p</i> = 0.12 no versus ≥90% tenofovir.</p><p>NA, not applicable.</p

Creatinine, phosphate, and haemoglobin toxicity.

<p><i>p</i>-Values from Wilcoxon rank sum tests (continuous) or chi-squared tests (categorical; exact tests used where <5% in any cell). Consecutive creatinine or phosphate values were abnormal in only two out of 14 children, neither of whom were exposed to tenofovir in utero. Few other laboratory abnormalities were observed: alanine transaminase (ALT), 12/364 measured; aspartate transaminase (AST), 21/344; low sodium, 73/364; low potassium, one out of 360; low calcium, eight out of 389. All abnormalities were grade 1 apart from four grade 2 and one grade 4 hyponatraemia.</p>a<p>Excludes <i>n = </i>9 with 22%–89% in utero exposure to tenofovir from comparison.</p>b<p>Grade 1 phosphate is ≥3.5 to <4.5 mg/dl (≥1.13 to <1.45 mmol/l) under 1 y of age; and ≥3.0 to <3.5 mg/dl (≥0.97 to <1.13 mmol/l) over 1 y of age.</p>c<p>See <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001217#pmed.1001217.s001" target="_blank">Table S1</a> for toxicity grades for haemoglobin and neutrophils in HIV-uninfected infants and children.</p><p>ULN, upper limit of normal.</p

Changes in height, weight, head circumference, and MUAC z-scores with age in HIV-exposed infants.

<p>Effects of tenofovir exposure on the different outcomes were similar adjusting for other factors at birth in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001217#pmed-1001217-t001" target="_blank">Table 1</a>; these cannot confound the relationship between growth and tenofovir exposure as there were no significant differences in these factors according to in utero tenofovir.</p>a<p>Would expect mean (standard deviation [SD]) of 0 (one) in a normal population: baseline is birth for weight and head circumference for age, week 12 for MUAC for age, and week 48 for height for age.</p>b<p>Predicted z-scores estimated from the fixed-effects population average fitted model at the ages above and back-transformed into sex-specific weights using the z-score formula.</p>c<p>Median (IQR) per child with 0% or ≥90% in utero tenofovir exposure same as the whole group.</p>d<p>Identical changepoints identified using profile log-likelihood as for the whole group.</p>e<p><i>p</i>-Value from a 2 degree of freedom (df) Wald test (1 df for head circumference) comparing time trends before and after changepoint.</p>f<p>Driven by estimated small decline in height for age from 48–120 wk (and greater height for age at 48 wk) in those with ≥90% tenofovir in utero exposure (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001217#pmed-1001217-g002" target="_blank">Figure 2</a>): <i>p</i> = 0.38 comparing height-for-age trajectories after 120 wk.</p>g<p><i>p</i>-Value from a 3 df Wald test (2 df for head circumference).</p

Flow diagram.

<p>*, Medical abortion is not generally legal in either Uganda or Zimbabwe. **, More pregnancies on tenofovir occurred in the first 3 y after ART initiation when the proportion of pregnancies ending in miscarriage/termination and stillbirth were higher and rates of live-births were lower.</p

Height-for-age and weight-for-age z-scores in infants born to HIV-infected mothers taking ART.

<p>Numbers and mean (95% CI) based on the closest measurement per child to scheduled visit weeks, which were at 6, 12, 24 wk, and then 24-weekly.</p

Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

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 difference 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&lt;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, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.)