Jennifer Cocohoba

Raltegravir: The first HIV integrase inhibitor

BACKGROUND The availability of new classes of antiretroviral drugs has made it possible for HIV-infected individuals who are highly treatment experienced to achieve the goals of immunologic recovery and virologic suppression. Raltegravir is the first integrase inhibitor to be approved by the US Food and Drug Administration for use in antiretroviral treatment- experienced adult patients with viral resistance. OBJECTIVE This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, tolerability, resistance profile, drug interactions, and dosing and administration of raltegravir. METHODS Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to July 2008 were conducted using the terms integrase, raltegravir, and MK-0518. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (1998-2008); Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2007); International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (2001-2007); and European AIDS Conference (2001-2007) were also searched. RESULTS Raltegravir blocks HIV replication by inhibiting essential strand-transfer activities of integrase. Raltegravir is rapidly absorbed, with a median T(max) of approximately 4 hours in the fasting state. No dose adjustment is recommended in patients with moderate renal or hepatic insufficiency, and raltegravir may be taken without regard to meals. In Phase II studies in treatment-naive patients, raltegravir had efficacy similar to that of standard initial therapies. In 2 interrelated Phase III clinical studies in treatment-experienced patients with drug-resistant disease, the addition of raltegravir to an optimized background regimen significantly lowered HIV RNA compared with optimized background treatment alone (62.1% vs 32.9%, respectively; P < 0.001). Raltegravir was generally well tolerated. The most common adverse effects reported in Phase II/III trials in treatment-experienced patients were diarrhea (16.6%), nausea (9.9%), and headache (9.7%). Cytochrome P450-related drug interactions are not expected, as raltegravir is not a CYP substrate, inducer, or inhibitor. However, to prevent failure of raltegravir, the drug should not be coadministered with rifampin. CONCLUSION Raltegravir is a potent and generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretrovirals.

Effects of HIV antiretrovirals on the pharmacokinetics of hormonal contraceptives

Objectives To review available information on pharmacokinetic effects of HIV antiretrovirals on hormonal contraceptives. Methods A PubMed search was conducted from 1964 to 2006 using each antiretroviral generic name and the keywords contraceptive, contraception, ethinyl oestradiol, oestrogen, and progestin. Abstracts from the annual Conference on Retroviruses and Opportunistic Infections and International AIDS Society Conferences from 1998–2006 as well as package product inserts were reviewed for completeness. Results Antiretroviral regimens containing protease inhibitors and non-nucleoside reverse transcriptase inhibitors may decrease the area under the curve (AUC) levels of steroids released by hormonal contraceptives. Some antiretroviral-hormonal contraceptive pairs do not decrease steroid hormone levels. Conclusion Pharmacokinetic interactions of antiretrovirals on hormonal contraceptives are specific to the type of antiretroviral and hormonal contraceptive being utilized. HIV-positive women may be counselled to use dual methods of hormonal and barrier contraception to prevent pregnancy with maximal efficacy as well as to reduce possibility of HIV transmission. Oral contraceptives might be administered with non-ritonavir boosted atazanavir or non-ritonavir boosted indinavir without a loss of contraceptive efficacy. Depot medroxyprogesterone acetate may be safe to administer with efavirenz, nevirapine, and nelfinavir. However, further studies are needed to determine the clinical relevance of the interactions between hormonal contraceptives and antiretrovirals and to explore potential dose adjustments to improve contraceptive efficacy.

Valganciclovir: An Advance in Cytomegalovirus Therapeutics

OBJECTIVE: To review the pharmacology, pharmacokinetics, and preliminary clinical data for valganciclovir, a new oral agent for the therapy of cytomegalovirus (CMV) retinitis. DATA SOURCES: Relevant literature was extracted via MEDLINE/PUBMED and searchable abstracts from infectious diseases conferences covering the period from January 1990 to April 2002. Tertiary references provided background information. DATA SYNTHESIS: Current standard treatment for CMV retinitis consists of intravenous therapy, intraocular implant, and intraocular injection. The low bioavailability of oral ganciclovir restricts its use to prophylaxis and maintenance treatment. Oral valganciclovir, recently approved for both induction and maintenance therapy of CMV retinitis, may fill a niche for this disease. CONCLUSIONS: Although only 1 clinical study has been published for valganciclovir, its favorable pharmacokinetic profile, encouraging preliminary efficacy data, ease of administration, and lack of potential catheter-related complications make it a favorable option for the treatment of CMV retinitis in HIV-positive patients.

The impact of HIV clinical pharmacists on HIV treatment outcomes: a systematic review

Objective Due to the rapid proliferation of human immunodeficiency virus (HIV) treatment options, there is a need for health care providers with knowledge of antiretroviral therapy intricacies. In a HIV multidisciplinary care team, the HIV pharmacist is well-equipped to provide this expertise. We conducted a systematic review to assess the impact of HIV pharmacists on HIV clinical outcomes. Methods We searched six electronic databases from January 1, 1980 to June 1, 2011 and included all quantitative studies that examined pharmacist’s roles in the clinical care of HIV-positive adults. Primary outcomes were antiretroviral adherence, viral load, and CD4+ cell count and secondary outcomes included health care utilization parameters, antiretroviral modifications, and other descriptive variables. Results Thirty-two publications were included. Despite methodological limitation, the involvement of HIV pharmacists was associated with statistically significant adherence improvements and positive impact on viral suppression in the majority of studies. Conclusion This systematic review provides evidence of the beneficial impact of HIV pharmacists on HIV treatment outcomes and offers suggestions for future research.

Increase in single-tablet regimen use and associated improvements in adherence-related outcomes in HIV-infected women.

Introduction:The use of single-tablet antiretroviral therapy (ART) regimens and its implications on adherence among HIV-infected women have not been well described. Methods:Participants were enrolled in the Womens Interagency HIV Study, a longitudinal study of HIV infection in US women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006–2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen using a case-crossover design. Results:We included 15,523 person-visits, representing 1727 women (53% black, 29% Hispanic, 25% IDU, median age 47). Use of single-tablet regimens among ART users increased from 7% in 2006% to 27% in 2013; adherence increased from 78% to 85% during the same period (both P < 0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers. Conclusions:Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits.

Consistency of initial antiretroviral therapy with HIV treatment guidelines in a US cohort of HIV-infected women.

Background:HIV treatment guidelines define optimal initial antiretroviral therapy (ART). Objective:To characterize initial ART used by a cohort of HIV-infected women according to US HIV treatment guidelines and determine whether regimen characteristics predict short-term outcomes. Methods:Initial ART self-reported by Womens Interagency HIV Study (WIHS) participants. Regimens were classified as guideline consistent (GC), guideline not recommended (GNR), or unlisted. Univariate and multivariate logistic regression was used to analyze factors associated with guideline category. Results:Two hundred seventeen WIHS participants initiated ART during the study period. Fifty-three percent reported use of GC ART, 17% reported GNR ART, and 30% reported ART unlisted in guidelines. Study site, higher pretreatment CD4 cell count, lower HIV RNA level, and initiation before 2001 were associated with use of GNR regimens. GC ART users had a higher rise in CD4 cell counts and more frequent undetectable HIV-1 RNA levels 2 years after initiation compared with those GNR (P = 0.0003) or unlisted initial ART. Conclusions:A higher than expected proportion of WIHS participants reported using initial ART not recommended by HIV treatment guidelines, although this decreased over time. Use of such regimens was associated with a higher incidence of switching and poorer short-term immunologic and virologic outcomes.

Tipranavir: A Protease Inhibitor for HIV Salvage Therapy

Objective: TO review the efficacy, safety, pharmacology, virology, pharmacokinetics, and resistance of the nonpeptidic protease inhibitor (PI) tipranavir. Data Sources and Study Selection: A PubMed search (1966–February 2006) was conducted using the key words tipranavir or PNU-140690, with the limitation of English-language reports. Pharmacokinetic and randomized clinical trials originating from major HIV conferences, such as the Conference on Retroviruses and Opportunistic Infections, International AIDS Society, European AIDS Conference, and Interscience Conference on Antimicrobial Agents and Chemotherapy, published only in abstract form, from 2000 to February 2006, were reviewed for relevance and included in this review. Data Synthesis: Phase III studies have shown that tipranavir is effective in the treatment of PI-resistant HIV compared with other PI-containing regimens. Adverse effects associated with tipranavir/ritonavir therapy include gastrointestinal reactions, hepatotoxicity, and elevations in cholesterol and triglyceride levels. Resistance data suggest that tipranavir/ritonavir should be reserved for salvage therapy in antiretroviral-experienced patients who have previously failed standard PI therapies. The potential for hepatotoxicity and drug interactions and the expense of tipranavir due to required ritonavir boosting may limit its widespread use. Conclusions: Tipranavir/ritonavir is an essential addition to the antiretroviral armamentarium for HIV-infected patients with limited treatment options.

The Impact of the AIDS Drug Assistance Program (ADAP) on Use of Highly Active Antiretroviral and Antihypertensive Therapy Among HIV-Infected Women

Objectives: To evaluate the association between enrollment into an AIDS Drug Assistance Program (ADAP) and use of highly active antiretroviral therapy (HAART) and antihypertensive therapy. Methods: Cross-sectional analyses of data were performed on HAART-eligible women enrolled in the California (n = 439), Illinois (n = 168), and New York (n = 487) Womens Interagency HIV Study sites. A subset of HIV-infected women with hypertension (n = 395) was also analyzed. Unadjusted and adjusted backward stepwise elimination logistic regression measured the association between demographic, behavioral, and health service factors and nonuse of HAART or antihypertensive medication. Results: In adjusted analysis of HAART nonuse, women without ADAP were significantly more likely not to use HAART (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.5-3.7) than women with ADAP. In adjusted analysis of antihypertensive medication nonuse, women without ADAP had an increased but not significant odds of antihypertensive medication nonuse (OR, 2.4; 95% CI, 0.93-6.0) than women with ADAP. Conclusions: Government-funded programs for prescription drug coverage such as ADAP may play an important role in how HIV-positive women access and use essential medications for chronic diseases.

Pharmacist counseling in a cohort of women with HIV and women at risk for HIV

Background and methods Achieving high adherence to antiretroviral therapy for human immunodeficiency virus (HIV) is challenging due to various system-related, medication-related, and patient-related factors. Community pharmacists can help patients resolve many medication-related issues that lead to poor adherence. The purpose of this cross-sectional survey nested within the Women’s Interagency HIV Study was to describe characteristics of women who had received pharmacist medication counseling within the previous 6 months. The secondary objective was to determine whether HIV-positive women who received pharmacist counseling had better treatment outcomes, including self-reported adherence, CD4+ cell counts, and HIV-1 viral loads. Results Of the 783 eligible participants in the Women’s Interagency HIV Study who completed the survey, only 30% of participants reported receiving pharmacist counseling within the last 6 months. Factors independently associated with counseling included increased age (odds ratio [OR] 1.28; 95% confidence interval [CI] 1.07–1.55), depression (OR 1.75; 95% CI 1.25–2.45), and use of multiple pharmacies (OR 1.65; 95% CI 1.15–2.37). Patients with higher educational attainment were less likely to report pharmacist counseling (OR 0.68; 95% CI 0.48–0.98), while HIV status did not play a statistically significant role. HIV-positive participants who received pharmacist counseling were more likely to have optimal adherence (OR 1.23; 95% CI 0.70–2.18) and increased CD4+ cell counts (+43 cells/mm3, 95% CI 17.7–104.3) compared with those who had not received counseling, though these estimates did not achieve statistical significance. Conclusion Pharmacist medication counseling rates are suboptimal in HIV-positive and at-risk women. Pharmacist counseling is an underutilized resource which may contribute to improved adherence and CD4+ counts, though prospective studies should be conducted to explore this effect further.

Impact of Health Insurance, ADAP, and Income on HIV Viral Suppression among US Women in the Women's Interagency HIV Study, 2006-2009

Background:Implementation of the Affordable Care Act motivates assessment of health insurance and supplementary programs, such as the AIDS Drug Assistance Program (ADAP) on health outcomes of HIV-infected people in the United States. We assessed the effects of health insurance, ADAP, and income on HIV viral load suppression. Methods:We used existing cohort data from the HIV-infected participants of the Womens Interagency HIV Study. Cox proportional hazards models were used to estimate the time from 2006 to unsuppressed HIV viral load (>200 copies/mL) among those with Medicaid, private, Medicare, or other public insurance, and no insurance, stratified by the use of ADAP. Results:In 2006, 65% of women had Medicaid, 18% had private insurance, 3% had Medicare or other public insurance, and 14% reported no health insurance. ADAP coverage was reported by 284 women (20%); 56% of uninsured participants reported ADAP coverage. After accounting for study site, age, race, lowest observed CD4, and previous health insurance, the hazard ratio (HR) for unsuppressed viral load among those privately insured without ADAP, compared with those on Medicaid without ADAP (referent group), was 0.61 (95% CI: 0.48 to 0.77). Among the uninsured, those with ADAP had a lower relative hazard of unsuppressed viral load compared with the referent group (HR, 95% CI: 0.49, 0.28 to 0.85) than those without ADAP (HR, 95% CI: 1.00, 0.63 to 1.57). Conclusions:Although women with private insurance are most likely to be virally suppressed, ADAP also contributes to viral load suppression. Continued support of this program may be especially critical for states that have not expanded Medicaid.