Laurie Andrews

Sustained benefit from a long-term antiretroviral adherence intervention. Results of a large randomized clinical trial.

Objective:To assess the efficacy of 2 adherence interventions, medication managers (MM) and medication alarms (ALR), among antiretroviral (ARV)-naive persons with HIV initiating ARV therapy. Methods:A multicenter, randomized, adherence intervention clinical trial was conducted among participants coenrolled in an HIV ARV strategy study for ARV-naive individuals. Sites were assigned by cluster randomization using a 2 × 2 factorial design to administer MM, ALR, MM + ALR, or neither (control). MM participants received individualized, structured, long-term adherence support from trained MMs. ALR participants received individually programmed ALR alarms for use throughout the study. Results:The 928 participants, followed a median of 30 months, included 22% women and 75% nonwhites; the median baseline CD4 count was 155 cells/mm3. First virologic failure was 13% lower in all MM versus no-MM groups (P = 0.13) and 28% lower in MM versus no-MM subgroups randomized to 2-class ARV arms in the parent ARV study (P = 0.01). MM (vs. no-MM) participants had significantly better CD4 cells count (P = 0.01) and adherence (P < 0.001) outcomes. ALR (vs. no-ALR) participants had worse virologic outcomes. Conclusion:This large randomized clinical trial demonstrated that interpersonal structured adherence support was associated with improved long-term medication adherence and virologic and immunologic HIV outcomes.

Interaction of methadone with didanosine and stavudine.

For opiate-dependent injection drug users infected with HIV, methadone therapy may facilitate adherence to complex highly active antiretroviral therapy (HAART) regimens. Current HAART regimens include one or more nucleoside analogues. We investigated the effects of methadone on the pharmacokinetics of the tablet formulation of didanosine (ddI) and of stavudine (d4T) in 17 study subjects on stable methadone therapy and in 10 untreated controls. Methadone treatment reduced the measured areas under the time-concentration curve (AUC0-6) by 63% for ddI (p =.04) and by 25% for d4T (p =.005) and the extrapolated AUCs for the full dosing interval (AUC0-12) by 57% for ddI (p =.11) and by 23% for d4T (p =. 02). Peak drug concentrations (Cmax) were reduced by 66% (p =.007) and 44% (p =.001) for ddI and d4T, respectively. The effects on AUC and Cmax appeared to result primarily from decreases in bioavailability. Methadone also delayed drug absorption. Trough levels for methadone did not differ significantly from those in historical controls, suggesting that ddI and d4T did not substantially alter methadone disposition. The results suggest that larger doses of the tablet formulation or an alternate formulation may be needed when didanosine is given to study subjects treated with methadone.

PROGRESS IN HIV THERAPEUTICS AND THE CHALLENGES OF ADHERENCE TO ANTIRETROVIRAL THERAPY

The impressive and gratifying advances in antiretroviral therapy have benefited many with HIV disease who are fortunate to have access to these complicated and expensive regimens. It is still early in the era of HAART, and the future of therapeutics is not clear. No other infectious disease has required lifelong therapy, and the challenges of equitable treatment of this chronic infectious disease are daunting; not the least among them is lifelong adherence to medications. To maximize the potential of each drug and drug combination, targeted efforts to increase and maintain excellent adherence in the real-world clinical setting are essential, and are second in importance only to the more widespread availability of HAART and continued development of new and more potent agents. The theoretical basis for improving adherence exists, but more substantial research is required. The aim of providing and maintaining therapeutic benefit necessitates that clinicians develop and employ practical and relevant strategies to support antiretroviral adherence. The marriage of biology and behavior that characterizes clinical care in HIV disease is nowhere more challenging for clinicians than in the issue of adherence, but also nowhere more gratifying.

Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction

Background:Effective antiretroviral treatment of opiate-addicted drug users with HIV infection often requires concomitant substance abuse treatment, commonly with methadone. Pharmacological interactions between antiretroviral drugs and methadone may result in opiate withdrawal or increased side effects. Objectives:To determine if atazanavir, a once-daily protease inhibitor and moderate inhibitor of P450 CYP3A4, exhibited pharmacokinetic interactions with (R)-methadone. Methods:Methadone pharmacokinetic parameters were measured in 16 patients on chronic methadone therapy prior to and after 14 days of daily administration of atazanavir. Steady-state pharmacokinetic values for total, (R)- (active) and (S)- (inactive) isomers of methadone were derived from plasma concentrations versus time data. Symptoms of opiate withdrawal and excess were monitored. Results:For the active isomer (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 [90% confidence interval (CI), 0.95–1.10] for the area under the concentration–time curve (AUC), 0.91 (90% CI, 0.84–1.00) for plasma maximal concentration and 1.11 (90% CI, 1.02–1.20) for plasma trough concentration. Confidence intervals for all three were within the no-effect or bioequivalence range of 0.80–1.25 for (R)-methadone. Inactive (S)-methadone was modestly reduced during atazanavir coadministration. Clinically relevant symptoms of opiate withdrawal or excess were not detected. Exposures to atazanavir were within range of previously reported values. Conclusions:No clinically relevant pharmacokinetic interactions were found between atazanavir and methadone. Dosage adjustment need not be recommended for either methadone or atazanavir when co-administered to patients treated for opiate abuse and HIV disease.

The Pharmacokinetics of Methadone Following Co-Administration with a Lamivudine/Zidovudine Combination Tablet in Opiate-Dependent Subjects

Methadone pharmacokinetics were determined in an open-label, within subject study in 16 methadone-maintained, non-HIV-infected subjects prior to and following administration of one lamivudine 150-mg/zidovudine 300-mg combination tablet to determine whether this antiretroviral therapy alters methadone serum concentrations. No significant differences in the mean area under the serum concentration-time curve (AUC(0-24h); 8,753 +/- 4,280 vs. 8,641 +/- 4,431 microg-h/L),oralclearance(CL/F;9.9 +/- 4.9vs. 10.3 +/- 5.5 L/h),oral volume of distribution (Vd/F; 647 +/- 465 vs. 481 +/- 305 L), maximum serum concentration (Cmax; 514 +/- 223 vs. 5,510 +/- 237 microg/L), or terminal elimination half-life (t 1/2; 55.3 +/- 61.0 vs. 35.0 +/- 17.5 h) were detected. These results suggest that methadone dose change is not likely to be necessary for patients treated with lamivudine/zidovudine combination pharmacotherapy.

Pharmacokinetic Interactions Between Buprenorphine/Naloxone and Tipranavir/Ritonavir in HIV-Negative Subjects Chronically Receiving Buprenorphine/Naloxone

HIV-infected patients with opioid dependence often require opioid replacement therapy. Pharmacokinetic interactions between HIV therapy and opioid dependence treatment medications can occur. HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone (BUP/NLX) therapy sequentially underwent baseline and steady-state pharmacokinetic evaluation of open-label, twice daily tipranavir 500 mg co-administered with ritonavir 200 mg (TPV/r). Twelve subjects were enrolled and 10 completed the study. Prior to starting TPV/r, the geometric mean BUP AUC(0-24h) and C(max) were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (> or = 7 days), these values were similar at 43.7 ng h/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC(0-24h) [68.7-14.7 ng h/mL; ratio=0.21 (90% CI 0.19-0.25)] and C(max) [4.75-0.94 ng/mL; ratio=0.20 (90% CI 0.17-0.23)]. The last measurable NLX concentration (C(last)) in the concentration-time profile, never measured in previous BUP/NLX interaction studies with antiretroviral medications, was decreased by 20%. Despite these pharmacokinetic effects on BUP metabolites and NLX, no clinical opioid withdrawal symptoms were noted. TPV steady-state AUC(0-12h) and C(max) decreased 19% and 25%, respectively, and C(min) was relatively unchanged when compared to historical control subjects receiving TPV/r alone. No dosage modification of BUP/NLX is required when co-administered with TPV/r. Though mechanistically unclear, it is likely that decreased plasma RTV levels while on BUP/NLX contributed substantially to the decrease in TPV levels. BUP/NLX and TPV/r should therefore be used cautiously to avoid decreased efficacy of TPV in patients taking these agents concomitantly.

Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir

Background:This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone (BUP/NLX) and lopinavir/ritonavir (LPV/r) in HIV-seronegative subjects chronically maintained on BUP/NLX. Methods:This study was an open labeled pharmacokinetic study in twelve HIV-seronegative subjects stabilized on at least 3 weeks of BUP/NLX therapy. Subjects sequentially underwent baseline and steady-state pharmacokinetic evaluation of once-daily LPV/r (800/200 mg). Results:Compared to baseline values, BUP AUC0-24h (46.8 vs. 46.2 ng*hr/mL) and Cmax (6.54 vs. 5.88 ng/mL) did not differ significantly after achieving steady-state LPV/r. Similar analyses of norBUP, the primary metabolite of BUP, demonstrated no significant difference in norBUP AUC0-24 hours (73.7 vs. 52.7 ng·h/mL); however, Cmax (5.29 vs. 3.11 ng/mL) levels were statistically different (P < 0.05) after LPV/r administration. Naloxone concentrations were similarly unchanged for AUC0-24 hours (0.421 vs. 0.374 ng·hr/mL) and Cmax (0.186 vs. 0.186 ng/mL). Using standardized measures, no objective opioid withdrawal was observed. The AUC0-24 hours and Cmin of LPV in this study did not significantly differ from historical controls (159.6 vs. 171.3 μg·hr/mL) and (2.3 vs. 1.3 μg/mL). Conclusions:The addition of LPV/r to stabilized patients receiving BUP/NLX did not affect buprenorphine pharmacokinetics but did increase the clearance of norbuprenorphine. Pharmacodynamic responses indicate that the altered norbuprenorphine clearance did not lead to opioid withdrawal. Buprenorphine/naloxone and LPV/r can be safely coadministered without need for dosage modification.

Tipranavir/ritonavir induction of buprenorphine glucuronide metabolism in HIV-negative subjects chronically receiving buprenorphine/naloxone.

Background: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/ naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP. Methods: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500 mg coadministered with ritonavir 200 mg (TPV/r). Results: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The Cmax of BUP-3G was 8.78 ± 5.23 ng/mL without TPV/r and increased to 12.7 ± 11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1 ± 19.4 (ng/mL) (h) without TPV/r and increased to 58. 6 ± 49.5 after steady state of TPV/r was achieved (p = .0966). In contrast, steady-state norBUP-3G AUC0–24 h (p = .0216) and Cmax (p = .0088) were significantly decreased in the presence of steady-state TPV/r. Conclusions and Scientific Significance: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G.

Pharmacokinetic Interactions between Buprenorphine/Naloxone and Raltegravir in Subjects Receiving Chronic Buprenorphine/Naloxone Treatment

Background: Interactions between human immuno-deficiency virus (HIV) and opioid-dependence therapies can occur. Objectives: We sought to determine whether such interactions occurred between buprenorphine/naloxone and raltegravir. Methods: We performed a within-subject open-labeled pharmacokinetic and pharmacodynamic study in 12 HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone therapy. Subjects underwent baseline and steady-state evaluation of the effect of raltegravir 400 mg BID on buprenorphine/naloxone parameters. Results: Compared with baseline values, buprenorphine AUC0–24 h (58.2 vs. 56.0 hr*ng/mL) and Cmax (7.37 vs. 6.60 ng/mL) did not differ significantly after achieving steady-state raltegravir. Similar analyses of norbuprenorphine, the primary metabolite of buprenorphine, demonstrated no significant difference after raltegravir administration. Naloxone concentrations were unchanged for AUC0–24 h (.595 vs. .581 hr*ng/mL), Cmax (.251 vs. .243 ng/mL) and Tmax (.75 vs.1.08 h). Objective opioid withdrawal was not observed. The AUC0–12 h and Cmax of raltegravir did not significantly differ from historical controls (5543 vs. 4428 h*ng/mL and 1070 vs. 1266 ng/mL), respectively. Conclusion: The addition of raltegravir to stabilized patients receiving buprenorphine/naloxone does not significantly affect buprenorphine/naloxone or raltegravir pharmacokinetic or pharmacodynamic parameters.

Integrated Tuberculosis/Human Immunodeficiency Virus Community-Based Case Finding in Rural South Africa: Implications for Tuberculosis Control Efforts

Summary Community-based integrated tuberculosis(TB)/human immunodeficiency virus (HIV) case finding demonstrates high yield for TB and HIV; a high proportion with drug resistance, without prior treatment; and the majority of tuberculosis in HIV-negative individuals, potentially representing a reservoir that is perpetuating the TB epidemic.