Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

Karim, Salim S. Abdool; Naidoo, Kogieleum; Grobler, Anneke; Padayatchi, Nesri; Baxter, Cheryl; Gray, Andy; Gengiah, Tanuja N.; Nair, Gonasagrie; Bamber, Sheila; Singh, Aarthi; Khan, Munira; Pienaar, Jacqueline; El‐Sadr, Wafaa; Friedland, Gerald; Karim, Quarraisha Abdool

doi:10.1056/nejmoa0905848

Cited by 568 publications

(409 citation statements)

References 18 publications

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“…[9] We also found that 71% of patients were HIV co-infected, which is slightly higher than the national average of 61%. [1] While this rate is very high, the proportion of TB patients starting treatment with an unknown HIV status has dropped considerably in recent years (from 41% in 2009 to just 7% in 2014) and the proportion of HIVpositive TB patients on ART has increased dramatically (from 16% in 2009 to 79% in 2014).…”

Section: Discussionmentioning

confidence: 63%

“…[4] Increasing CD4 counts [8] and timely ART initiation are known to reduce mortality during TB therapy. [9] With SA guidelines prioritising the initiation of all HIV/TB co-infected patients (regardless of CD4 count or clinical staging), [3] increases in ART coverage among TB patients are likely to continue, helping drive reductions in TB mortality.…”

Section: Discussionmentioning

confidence: 99%

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Outcomes of treatment of drug-susceptible tuberculosis at public sector primary healthcare clinics in Johannesburg, South Africa: A retrospective cohort study

et al. 2016

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Background.Despite the large number of tuberculosis (TB) patients treated in South Africa (SA), there are few descriptions in the published literature of drug-susceptible TB patient characteristics, mode of diagnosis or treatment outcomes in routine public sector treatment programmes. Objective. To enhance the evidence base for public sector TB treatment service delivery, we reported the characteristics of and outcomes for a retrospective cohort of adult TB patients at public sector clinics in the Johannesburg Metropolitan Municipality (JHB), SA. Methods. We collected medical record data for a retrospective cohort of adult (≥18 years) TB patients registered between 1 April 2011 and 31 March 2012 at three public sector clinics in JHB. Data were abstracted from National TB Programme clinic cards and the TB case registers routinely maintained at study sites. We report patient characteristics, mode of diagnosis, mode of treatment supervision, treatment characteristics, HIV status and treatment outcomes for this cohort. Results. A total of 544 patients were enrolled in the cohort. Most (86%) were new TB cases, 81% had pulmonary TB, 58% were smearpositive at treatment initiation and 71% were HIV co-infected. Among 495 patients with treatment outcomes reported, 80% (n=394) had successful outcomes, 11% (n=55) were lost to follow-up, 8% (n=40) died and 1% (n=6) failed treatment. Conclusions. Primary healthcare clinics in JHB are achieving relatively high rates of success in treating drug-susceptible TB. Missing laboratory results were common, including follow-up smears, cultures and drug susceptibility tests, making it difficult to assess adherence to guidelines and leaving scope for substantial improvements in record-keeping at the clinics involved.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Outcomes of treatment of drug-susceptible tuberculosis at public sector primary healthcare clinics in Johannesburg, South Africa: A retrospective cohort study

et al. 2016

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“…The mortality rate remains high even after completion of TB treatment, probably due to HIV disease. [6] Scaling up antiretroviral therapy (ART) to all HIV-infected TB patients is required to reduce HIV-related mortality among TB patients.…”

Section: Treat Tbmentioning

confidence: 99%

“…Initiating ART while on TB treatment saves lives, regardless of CD4 + count, and among persons with CD4 + counts <50 cells/µl, initiating ART soon after initiating TB treatment is essential to reduce mortality. [6,25] Decentralisation of ART services to primary healthcare clinics and integration with TB services have resulted in increasing numbers of TB patients initiating ART. In 2012, only 54% of HIV-positive TB patients were initiated on ART, [1] highlighting the need to scale up ART for TB patients further by scaling up nurse-initiated and managed ART training for all professional nurses.…”

Section: Tb/hiv Integrationmentioning

confidence: 99%

Tuberculosis control in South Africa: Successes, challenges and recommendations

et al. 2014

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“…Early initiation of antiretroviral therapy (ART) during TB therapy substantially reduces TB-related morbidity and mortality rates for coinfected patients (2,3), and the World Health Organization recommends that ART be started as soon as possible but within 8 weeks after the initiation of TB therapy (4). Simultaneously, the global emergence and increased dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have increased the need for novel anti-TB drugs with new mechanisms of action.…”

mentioning

confidence: 99%

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Svensson

Dooley

Karlsson

2014

Antimicrob Agents Chemother

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Early initiation of antiretroviral therapy (ART) during TB therapy substantially reduces TB-related morbidity and mortality rates for coinfected patients (2, 3), and the World Health Organization recommends that ART be started as soon as possible but within 8 weeks after the initiation of TB therapy (4). Simultaneously, the global emergence and increased dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have increased the need for novel anti-TB drugs with new mechanisms of action. Data from Eastern Europe indicate that multidrug resistance is approximately twice as common among patients with TB who have HIV, compared with patients without HIV (5), and a South African study found that 100% of patients with XDR-TB who were tested had HIV infections (6). Ensuring access to novel anti-TB compounds and determining safe and efficacious doses for coinfected patients must be priorities (7).The diarylquinoline bedaquiline (BDQ) (previously called TMC207) was recently approved for the treatment of MDR-TB and XDR-TB by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. The mechanism of action is novel and involves the inhibition of mycobacterial ATP synthase, leading to disrupted energy metabolism (8, 9). Phase II trials showed that BDQ significantly decreased the time to sputum culture conversion and increased the proportion of patients with negative culture results after 6 months of treatment, when added to a regimen of other anti-TB drugs (10,11). This treatment benefit was sustained at the end of the 120-week trial (12). The exposure-response relationship for BDQ is poorly characterized, but a recent study of early bactericidal activity detected a linear increase in bactericidal activity with increasing doses over 14 days of treatment (13). The main safety issue for BDQ is moderate QT prolongation; in addition, an unexplained increase in late deaths, compared to the placebo group, was observed in one phase II study in which all patients also received standard MDR-TB treatment, which resulted in a black-box warning in the U.S. label (12,14). In general, however, BDQ is better tolerated than other second-line TB drugs, the majority of which produce clinically significant and often treatment-limiting side effects (15). The current standard dosing regimen for BDQ is 2 weeks of 400 mg given daily, followed by 22 weeks of 200 mg administered three times per week. BDQ is extensively distributed to the tissues and has a multiphasic elimination pattern with a long terminal half-life (4 to 5 months) (16,17). It is mainly metabolized by the cytochrome P450 (CYP) enzyme CYP3A4 to a N-monodesmethyl metabolite, M2 (38). The activity of M2 against Mycobacterium tuberculosis is 3-to 6-fold weaker than the activity of BDQ, and there is concern that the metabolite may have a higher risk of toxicity (39). M2, though, circulates at much lower concentrations than the parent drug in humans. M2 is further primarily demethylated to the M3 metabolite, likely also by CYP3A4 (11,18).Ne...

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Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

Cited by 568 publications

References 18 publications

Outcomes of treatment of drug-susceptible tuberculosis at public sector primary healthcare clinics in Johannesburg, South Africa: A retrospective cohort study

Outcomes of treatment of drug-susceptible tuberculosis at public sector primary healthcare clinics in Johannesburg, South Africa: A retrospective cohort study

Tuberculosis control in South Africa: Successes, challenges and recommendations

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

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