[Show abstract][Hide abstract] ABSTRACT: Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured.
This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir.
Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations.
Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.
PLoS ONE 01/2014; 9(1):e84866. DOI:10.1371/journal.pone.0084866 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In most low-and middle-income countries, prote-ase inhibitors (PIs), combined with low-dose ritonavir to enhance pharmacokinetics, form the backbone of second-line ART regimens, with lopinavir/ritonavir (LPV/r) being the most common formulation used. Unfortunately, rifampicin (RMP) signifi cantly reduces the plasma concentrations of all known PIs by 75–95% by induction of cytochrome 3A4 (CYP3A4) enzymes. 6 Attempts to overcome this adverse drug-drug inter-action by either increasing the PI dose or altering the dose of RMP have been thwarted by hepatotoxic-ity, 7 and such approaches are in any case incompatible with large-scale and decentralised public sector roll-out of ART. Rifabutin (RBT) is an attractive alternative rifamy-cin to RMP, as it is a less potent inducer of CYP3A4, 8 and the drug can be combined with most unboosted and boosted PIs without PI dose adjustment. RBT is recommended at a standard dose of 300 mg daily for the prophylaxis and treatment of Mycobacterium avium complex and the treatment of drug-susceptible TB. Plasma concentrations of RBT are increased in the presence of PIs; 6 dose adjustments are therefore rec-ommended when RBT is combined with a PI. The 1998 guidelines of the US Centers for Disease Control and Prevention recommended that the dose of RBT be reduced from 300 mg to 150 mg in the presence of a PI, 9 and in 2004 that a dose of 150 mg two or three times a week should be used in combination with LPV/r. 10 However, recent reports have shown that in-termittent dosing is suboptimal and can result in in-adequate rifamycin levels that, in turn, can lead to TB relapse and acquired rifamycin resistance. 11–14 A protocol was therefore written with the primary aim of comparing the plasma concentrations of two different doses of RBT (150 mg three times per week and 150 mg daily) in patients with HIV-associated TB who initiated ART with LPV/r in South Africa and Viet Nam. Because of the interest in the use of RBT with non-nucleoside reverse transcriptase inhibitors (NNRTIs), the study protocol also included the study of different doses of RBT (600 mg, 450 mg and 300 mg) in combination with efavirenz (EFV) or nevirapine. The study protocol in South Africa (Agence nationale de recherches sur le sida [ANRS] 12150a, clinical trial reg-istry number NCT00640887) was fi nal ised in August 2007 and approved in June 2008. The study proto-col in Viet Nam (ANRS 12150b, clinical trial registry InternaƟ onal Union Against Tuberculosis and Lung Disease Health soluƟ ons for the poor
[Show abstract][Hide abstract] ABSTRACT: Cryptococcal infection is a frequent cause of mortality in Cambodian HIV-infected patients with CD4+ count ≤100 cells/µl. This study assessed the cost-effectiveness of three strategies for cryptococcosis prevention in HIV-infected patients.
A MARKOV DECISION TREE WAS USED TO COMPARE THE FOLLOWING STRATEGIES AT THE TIME OF HIV DIAGNOSIS: no intervention, one time systematic serum cryptococcal antigen (CRAG) screening and treatment of positive patients, and systematic primary prophylaxis with fluconazole. The trajectory of a hypothetical cohort of HIV-infected patients with CD4+ count ≤100 cells/µl initiating care was simulated over a 1-year period (cotrimoxazole initiation at enrollment; antiretroviral therapy within 3 months). Natural history and cost data (US$ 2009) were from Cambodia. Efficacy data were from international literature.
In a population in which 81% of patients had a CD4+ count ≤50 cells/ µl and 19% a CD4+ count between 51-100 cells/µl, the proportion alive 1 year after enrollment was 61% (cost $ 472) with no intervention, 70% (cost $ 483) with screening, and 72% (cost $ 492) with prophylaxis. After one year of follow-up, the cost-effectiveness of screening vs. no intervention was US$ 180/life year gained (LYG). The cost-effectiveness of prophylaxis vs. screening was $ 511/LYG. The cost-effectiveness of prophylaxis vs. screening was estimated at $1538/LYG if the proportion of patients with CD4+ count ≤50 cells/µl decreased by 75%.
In a high endemic area of cryptococcosis and HIV infection, serum CRAG screening and prophylaxis are two cost effective strategies to prevent AIDS associated cryptococcosis in patients with CD4+ count ≤100 cells/µl, at a short-term horizon, screening being more cost-effective but less effective than prophylaxis. Systematic primary prophylaxis may be preferred in patients with CD4+ below 50 cells/µl while systematic serum CRAG screening for early targeted treatment may be preferred in patients with CD4+ between 51-100 cells/µl.
PLoS ONE 11/2010; 5(11):e13856. DOI:10.1371/journal.pone.0013856 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Efavirenz is used for the antiretroviral treatment of HIV/tuberculosis-coinfected patients in developing countries. A switch to nevirapine is regularly carried out because of the cost and side effects of efavirenz. Pharmacokinetic studies suggested that nevirapine should be initiated at full dose when used as a substitute for efavirenz.
The aim of this study was to measure the cumulative incidence of adverse events (AEs) related to nevirapine in patients switched from efavirenz to immediate full-dose nevirapine (FDN).
In 2001 an antiretroviral treatment programme was initiated with the first-line regimen stavudine, lamivudine and efavirenz. In 2003, the fixed-dose combination of stavudine, lamivudine and nevirapine was recommended. Thus, first-line therapy was changed and FDN was initiated when patients were switched from efavirenz to nevirapine.
Between April and December 2004, 394 patients were switched from efavirenz to FDN. The cumulative incidence of AEs related to nevirapine was 13.2% [95% confidence interval (CI) 10.2-16.7] and that of severe AEs was 8.9% (95% CI 6.5-11.9). In women the incidence of AEs was 17.6% (95% CI 12.1-24.3) and that of severe AEs was 12.2% (95% CI 7.7-18.2).
Our results indicate that an FDN switch from efavirenz does not appear to result in more AEs than when nevirapine is initiated with escalating doses. These data are particularly relevant in resource-limited settings.
HIV Medicine 07/2008; 9(7):514-8. DOI:10.1111/j.1468-1293.2008.00597.x · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The long-term maintenance of antiretroviral therapy (ART) remains an important issue, especially in limited-resource settings where additional barriers exist. A cross-sectional study was performed 24 months after ART initiation for patients treated in Cambodia in order to estimate the prevalence and identify determinants of non-adherence.
Adults receiving ART for 24 +/- 2 months were considered eligible for the study. Self-reported non-adherence was defined according to an algorithm based on six items. The questionnaire also assessed ART-related side effects and HIV disclosure. HIV-1 RNA plasma viral load was measured using real-time PCR. Multivariate rare events logistic regression analysis was used to identify independent factors associated with non-adherence.
A total of 346 patients participated in the study. At 24 months, 95% of patients were adherent, 80% had HIV RNA <40 copies/ml and 75% had CD4+ T-cell counts >200 cells/mm3. Virological success was significantly higher in adherent patients than in non-adherent patients (81% versus 56%, P=0.021). Living in a rural area, limited HIV disclosure and perceived lipodystrophy were independently associated with non-adherence.
At 24 months, adherence to ART was high and explained positive virological outcomes. In order to maintain adherence and long-term virological benefits, special attention should be given to patients living in rural areas, those with lipodystrophy-related symptoms and others who express difficulties disclosing their condition to close family members.
[Show abstract][Hide abstract] ABSTRACT: African and Asian cohort studies have demonstrated the feasibility and efficacy of HAART in resource-poor settings. The long-term virological outcome and clinico-immunological criteria of success remain important questions. We report the outcomes at 24 months of antiretroviral therapy (ART) in patients treated in a Médecins Sans Frontières/Ministry of Health programme in Cambodia.
Adults who started HAART 24 +/- 2 months ago were included. Plasma HIV-RNA levels were assessed by real-time polymerase chain reaction. Factors associated with virological failure were analysed using logistic regression.
Of 416 patients, 59.2% were men; the median age was 33.6 years. At baseline, 95.2% were ART naive, 48.9% were at WHO stage IV, and 41.6% had a body mass index less than 18 kg/m. The median CD4 cell count was 11 cells/microl. A stavudine-lamivudine-efavirenz-containing regimen was initiated predominantly (81.0%). At follow-up (median 23.8 months), 350 (84.1%) were still on HAART, 53 (12.7%) had died, six (1.4%) were transferred, and seven (1.7%) were lost to follow-up. Estimates of survival were 85.5% at 24 months. Of 346 tested patients, 259 (74.1%) had CD4 cell counts greater than 200 cells/microl and 306 (88.4%) had viral loads of less than 400 copies/ml. Factors associated with virological failure at 24 months were non-antiretroviral naive, an insufficient CD4 cell gain of less than 350 cells/microl or a low trough plasma ART concentration. In an intention-to-treat analysis, 73.6% of patients were successfully treated.
Positive results after 2 years of advanced HIV further demonstrate the efficacy of HAART in the medium term in resource-limited settings.
AIDS 12/2007; 21(17):2293-301. DOI:10.1097/QAD.0b013e32828cc8b7 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HAART efficacy was evaluated in a real-life setting in Phnom Penh (Médecins Sans Frontières programme) among severely immuno-compromised patients.
Factors associated with mortality and immune reconstitution were identified using Cox proportional hazards and logistic regression models, respectively.
From July 2001 to April 2005, 1735 patients initiated HAART, with median CD4 cell count of 20 (inter-quartile range, 6-78) cells/microl. Mortality at 2 years increased as the CD4 cell count at HAART initiation decreased, (4.4, 4.5, 7.5 and 24.7% in patients with CD4 cell count > 100, 51-100, 21-50 and < or = 20 cells/microl, respectively; P < 10). Cotrimoxazole and fluconazole prophylaxis were protective against mortality as long as CD4 cell counts remained < or = 200 and < or = 100 cells/microl, respectively. The proportion of patients with successful immune reconstitution (CD4 cell gain > 100 cells/microl at 6 months) was 46.3%; it was lower in patients with previous ART exposure [odds ratio (OR), 0.16; 95% confidence interval (CI), 0.05-0.45] and patients developing a new opportunistic infection/immune reconstitution infection syndromes (OR, 0.71; 95% CI, 0.52-0.98). Similar efficacy was found between the stavudine-lamivudine-nevirapine fixed dose combination and the combination stavudine-lamivudine-efavirenz in terms of mortality and successful immune reconstitution. No surrogate markers for CD4 cell change could be identified among total lymphocyte count, haemoglobin, weight and body mass index.
Although CD4 cell count-stratified mortality rates were similar to those observed in industrialized countries for patients with CD4 cell count > 50 cells/microl, patients with CD4 cell count < or = 20 cells/microl posed a real challenge to clinicians. Widespread voluntary HIV testing and counselling should be encouraged to allow HAART initiation before the development of severe immuno-suppression.
AIDS 01/2007; 21(3):351-9. DOI:10.1097/QAD.0b013e328012c54f · 5.55 Impact Factor