Plasma nevirapine concentrations predict virological and adherence failure in Kenyan HIV-1 infected patients with extensive antiretroviral treatment exposure

Treatment failure is a key challenge in the management of HIV-1 infection. We conducted a mixed-model survey of plasma nevirapine (NVP) concentrations (cNVP) and viral load in order to examine associations with treatment and adherence outcomes among Kenyan patients on prolonged antiretroviral therapy (ART). Blood plasma was collected at 1, 4 and 24 hours post-ART dosing from 58 subjects receiving NVP-containing ART and used to determine cNVP and viral load (VL). Median duration of treatment was 42 (range, 12–156) months, and 25 (43.1%) of the patients had virologic failure (VF). cNVP was significantly lower for VF than non- VF at 1hr (mean, 2,111ng/ml vs. 3,432ng/ml, p = 0.003) and at 4hr (mean 1,625ng/ml vs. 3,999ng/ml, p = 0.001) but not at 24hr post-ART dosing. Up to 53.4%, 24.1% and 22.4% of the subjects had good, fair and poor adherence respectively. cNVP levels peaked and were > = 3μg.ml at 4 hours in a majority of patients with good adherence and those without VF. Using a threshold of 3μg/ml for optimal therapeutic nevirapine level, 74% (43/58), 65.5% (38/58) and 86% (50/58) of all patients had sub-therapeutic cNVP at 1, 4 and 24 hours respectively. cNVP at 4 hours was associated with adherence (p = 0.05) and virologic VF (p = 0.002) in a chi-square test. These mean cNVP levels differed significantly in non-parametric tests between adherence categories at 1hr (p = 0.005) and 4hrs (p = 0.01) and between ART regimen categories at 1hr (p = 0.004) and 4hrs (p<0.0001). Moreover, cNVP levels correlated inversely with VL (p< = 0.006) and positively with adherence behavior. In multivariate tests, increased early peak NVP (cNVP4) was independently predictive of lower VL (p = 0.002), while delayed high NVP peak (cNVP24) was consistent with increased VL (p = 0.033). These data strongly assert the need to integrate plasma concentrations of NVP and that of other ART drugs into routine ART management of HIV-1 patients

Co-Infection Burden of Hepatitis C Virus and Human Immunodeficiency Virus among Injecting Heroin Users at the Kenyan Coast.

Injection drug use is steadily rising in Kenya. We assessed the prevalence of both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infections among injecting heroin users (IHUs) at the Kenyan Coast.A total of 186 IHUs (mean age, 33 years) from the Omari rehabilitation center program in Malindi were consented and screened for HIV-1 and HCV by serology and PCR and their CD4 T-cells enumerated by FACS.Prevalence of HIV-1 was 87.5%, that of HCV was 16.4%, co-infection was 17.9% and 18/152 (11.8%) were uninfected. Only 5.26% of the HIV-1 negative injectors were HCV positive. Co-infection was higher among injectors aged 30 to 40 years (20.7%) and among males (22.1%) than comparable groups. About 35% of the injectors were receiving antiretroviral treatment (ART). Co-infection was highest among injectors receiving D4T (75%) compared to those receiving AZT (21.6%) or TDF (10.5%) or those not on ART (10.5%). Mean CD4 T-cells were 404 (95% CI, 365 - 443) cells/mm3 overall, significantly lower for co-infected (mean, 146; 95% CI 114 - 179 cells/mm3) than HIV mono infected (mean, 437, 95% CI 386 - 487 cells/mm3, p<0.001) or uninfected (mean, 618, 95% CI 549 - 687 cells/mm3, p<0.001) injectors and lower for HIV mono-infected than uninfected injectors (p=0.002). By treatment arm, CD4 T-cells were lower for injectors receiving D4T (mean, 78; 95% CI, 0.4 - 156 cells/mm3) than TDF (mean 607, 95% CI, 196 - 1018 cells/mm3, p=0.005) or AZT (mean 474, 95% CI -377 - 571 cells/mm3, p=0.004).Mono and dual infections with HIV-1 and HCV is high among IHUs in Malindi, but ART coverage is low. The co-infected IHUs have elevated risk of immunodeficiency due to significantly depressed CD4 T-cell numbers. Coinfection screening, treatment-as-prevention for both HIV and HCV and harm reduction should be scaled up to alleviate infection burden

Trajectory plasma nevirapine concentrations and association with viral load.

<p>Plasma nevirapine concentration (cNVP) is compared for various groups over 24 hour period according to adherence (A:- open circle, good adherence; closed diamonds, fair adherence; open triangle, poor adherence; solid line, mean), and according to virologic response or gender (B:- open diamond, virologic failure; closed circle, virologic success or non-virologic failure; closed triangle, male; crosses, female). Patients with good and fair adherence and those with virologic success (non-virologic failure) had peak cNVP at 4 hours while cNVP for virologic failure patients started low at 1hr and peaked later at 24hrs. Significant inverse correlations are observed between same day viral load with cNVP at 1 hour (C) and at 4 hours (D). Circles, virologic success; triangles, virologic failure.</p

Peak cNVP predict virologic response as much as does VL in a multivariate analysis.

<p>Peak cNVP predict virologic response as much as does VL in a multivariate analysis.</p

Peak nevirapine concentration is consistent with better adherence and viral load suppression.

<p>Peak nevirapine concentration is consistent with better adherence and viral load suppression.</p

Virologic treatment response of various categories of patients.

<p>Virologic treatment response of various categories of patients.</p

CD4 Counts across various categories of heroin injectors.

<p>CD4 T-cells are compared between treatment arms of injectors (A). ¶ Counts are significantly lower for the D4T- arm than for the AZT arm (p = 0.004), TDF (p = 0.005) or the ART- (p<0.001) arm and lower for the sub-optimal ART than ART- (p = 0.023) arm. All subjects in the ‘ART-’ arm were not infected (NI) by either virus. Mean CD4 counts are compared between infection statuses (B). These are significantly lower for co-infected than HIV-1 mono infected injectors as shown. §Shows significantly lower CD4 counts for HIV mono-infected than NI injectors (p = 0.002). CD4 data is compared between age groups of the different infection statuses (C). No significant (NS) difference was observed. *Co-infected injectors had much lower CD4 levels compared to other infection categories in any age group. Only one injector was HCV mono-infected (horizontal bar in the >30–40 years category). CD4 Counts were not significantly different between genders of injectors (D). ART, antiretroviral treatment; CTX, cotrimoxazole (septrin); ART-, No ART; Uk, unknown ART status; Sub, sub optimal ART.</p

CD4 T-cell counts compared by various categories of heroin injectors who were screened for both HIV and HCV.

<p>Legend of table:</p><p>^† P-value is significant at level shown comparing mean CD4 between infection statuses or between treatment arms.</p><p>^a No qualifying subjects.</p><p>^b Confidence Interval (CI) is not applicable. ART, antiretroviral treatment. Only one subject (aged 31-40yrs, CD4 T-cells of 287 counts/mm³) was HCV mono-infected, and is excluded from this table. Sub-optimal ART cases are IHUs with unexplained use of single-drug ART regimen.</p><p>CD4 T-cell counts compared by various categories of heroin injectors who were screened for both HIV and HCV.</p