Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.

Background

We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.

Methods

To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here.

Results

Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006).

Conclusions

The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.

Background

Nosocomial transmission has been described in extensively drug resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about rates of drug-resistant TB among healthcare workers (HCWs) in TB and HIV endemic settings.

Objective

To estimate rates of multi-drug resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among HCWs in KwaZulu-Natal (KZN), South Africa.

Design

Retrospective study of drug-resistant TB patients admitted for the initiation of drug-resistant TB therapy between 2003 and 2008.

Setting

A public TB referral hospital in KZN, South Africa.

Participants

HCWs admitted with MDR-TB (N=203) or XDR-TB (N=28) were compared with non-HCWs admitted with MDR-TB (N=3807) or XDR-TB (N=344).

Measurements

Hospital admission rates, hospital admission incidence rate ratios.

Results

Estimated incidence of MDR-TB hospitalization was 64.8/100,000 for HCWs versus 11.9/100,000 for non-HCWs (I.R.R. 5.56 95% C.I. 4.87–6.35). Estimated incidence of XDR-TB hospitalizations was 7.2/100,000 among HCWs versus 1.1/100,000 in non-HCWs (I.R.R. 6.69 95% C.I. 4.38–10.20). A higher percentage of HCWs than non-HCWs with MDR-TB or XDR-TB were female (78% vs. 47%, p<0.001) and fewer HCWs reported previous TB treatment (41% vs. 92%, p<0.001). Prevalence of HIV infection did not differ between HCW and non-HCW (55% vs. 57%, p=0.71), but a higher percentage of HIV infected HCWs were on antiretroviral medications (63% vs. 47%, p<0.001).

Conclusion

HCWs in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB compared to non-HCWs. The increased risk may be explained by occupational exposure and not by other risk factors, underlining the urgent need for TB infection control programs.

Primary Funding Source

No funding was received for this study

To determine whether women in KwaZulu-Natal, South Africa, with drug-resistant tuberculosis (TB) were more likely than men to have extensively drug-resistant TB, we reviewed 4,514 adults admitted during 2003–2008 for drug-resistant TB. Female sex independently predicted extensively drug-resistant TB, even after we controlled for HIV infection. This association needs further study.

Despite high mortality rates in tuberculosis patients with HIV co-infection, there is continued controversy on when to initiate antiretroviral therapy (ART) in these patients.

Methods

We conducted an open-label randomized controlled trial in Durban, South Africa to determine optimal timing of ART initiation in relation to TB treatment. Acid-fast bacilli (AFB) smear positive tuberculosis patients with HIV infection and CD4+ counts <500 cells/mm3 (n=642) were randomized to one of two integrated treatment arms (ART initiation during tuberculosis treatment) or to a sequential treatment arm (ART initiation upon tuberculosis treatment completion). Participants received standard tuberculosis therapy, cotrimoxazole prophylaxis and once daily didanosine, lamivudine and efavirenz ART regimen. The primary endpoint was all-cause mortality.

Results

This analysis compares data from the sequential treatment arm and the combined integrated treatment arms up to 1 September 2008, when the Safety Monitoring Committee recommended halting the sequential treatment arm. Demographic, clinical and laboratory characteristics at baseline and adverse event rates during follow-up were similar in the study arms. Mortality was 56% lower (hazard ratio: 0.44; 95% Confidence Interval: 21% to 75%; p = 0.003) in the integrated arm (5.4 per 100 person-years (25 deaths; n=429)) compared to sequential arm (12.1 per 100 person-years (27 deaths; n=213)). Mortality rates were lower regardless of CD4+ count level.

Conclusions

Initiating ART during tuberculosis treatment in AFB positive patients with HIV co-infection and CD4+ counts <500 cells/mm3 significantly improves survival and provides further impetus for the integration of tuberculosis and AIDS services.

SUMMARY

Setting

Multidrug-resistant tuberculosis (MDR TB) has emerged as a significant public health threat in South Africa.

Objective

To describe treatment outcomes and determine risk factors associated with unfavorable outcomes among MDR-TB patients admitted to the provincial TB referral hospital in KwaZulu-Natal province, South Africa.

Design

Retrospective observational study of MDR TB patients admitted from 2000–2003.

Results

Of 1209 MDR TB patients with documented treatment outcomes, 491 (41%) were cured, 35 (3%) completed treatment, 208 (17%) failed treatment, 223 (18%) died and 252 (21%) defaulted. 52% of patients with known HIV status were HIV-infected. Treatment failure, death and default each differed in their risk factors. Greater baseline resistance (AOR 2.3–3.0), prior TB (AOR 1.7), and diagnosis in years 2001, 2002 or 2003 (AOR 1.9–2.3) were independent risk factors for treatment failure. HIV co-infection was a risk factor for death (AOR 5.6) and both HIV (AOR 2.0) and male sex (AOR 1.9) were risk factors for treatment default.

Conclusion

MDR TB treatment outcomes in KwaZulu-Natal were substantially worse than those published from other MDR TB cohorts. Interventions, such as individualized treatment, concurrent antiretroviral therapy and decentralized MDR TB treatment must be considered to improve MDR TB outcomes in this high HIV-prevalence setting.

Time to detection of Mycobacterium tuberculosis in broth culture was examined for utility as a treatment efficacy end point. Of 146 patients in a phase IIB trial, a decreased mean time to detection was found in 5 with treatment failure. Time to detection in an analysis-of-covariance model was associated with lung cavities, less intensive treatment, and differences in the bactericidal effects of treatment regimens.

The intersecting HIV and Tuberculosis epidemics in countries with a high disease burden of both infections pose many challenges and opportunities. For patients infected with HIV in high TB burden countries, the diagnosis of TB, ARV drug choices in treating HIV-TB coinfected patients, when to initiate ARV treatment in relation to TB treatment, managing immune reconstitution, minimising risk of getting infected with TB and/or managing recurrent TB, minimizing airborne transmission, and infection control are key issues. In addition, given the disproportionate burden of HIV in women in these settings, sexual reproductive health issues and particular high mortality rates associated with TB during pregnancy are important. The scaleup and resource allocation to access antiretroviral treatment in these high HIV and TB settings provide a unique opportunity to strengthen both services and impact positively in meeting Millennium Development Goal 6.

Setting

A public tuberculosis (TB) referral hospital in KwaZulu-Natal, South Africa.

Objective

To present treatment outcomes of patients with extensively drug resistant tuberculosis (XDR-TB) patients and HIV co-infection with and without HAART.

Methods

Retrospective cohort study. Eligible patients had drug susceptibility testing that met a consensus definition for XDR-TB, and agreed to treatment. Therapy was based on drug susceptibilities, available medications, and patient tolerance.

Results

60 XDR-TB patients initiated therapy with a median number of 5.5 drugs. Of these 43 (72%) were HIV+, and 21 (49%) were on anti-retroviral therapy. 29 HIV infected patients (67%) had available CD4 counts; median CD4 count was 200.5 (S.D. 127.4). 31/60 patients (52%) had adverse events (AEs), and 17/60 patients (28%) had severe AEs. During follow-up, 12/60 (20%) experienced sputum culture conversion, while 25/60 (42%) patients died. None of the following was significantly associated with mortality: HIV status, previous MDR diagnosis or severe AEs.

Discussion

In this study it was possible to treat HIV/XDR-TB co-infected patients, and prolong survival in a resource limited setting. We highlight the challenges in treatment, including high frequencies of AEs and death. Expanded identification of cases, prompt referral for treatment, and attention to management of co-morbidities may facilitate successful treatment of in XDR-TB in HIV infected patients.

Background

Despite widely acknowledged WHO guidelines for the integration of TB and HIV services, heavily burdened countries have been slow to implement these and thus significant missed opportunities have arisen.

Discussion

The individual-centred, rights-based paradigm of the SA National AIDS Policy, remains dissonant with the compelling public-health approach of TB control. The existence of independent and disconnected TB and HIV services results in a wastage of scarce health resources, an increased burden on patients' time and finances, and ignores evidence of patients' preference for an integrated service. The current situation translates into a web of unacceptable, ongoing missed opportunities such as failure to maximize collaborative disease surveillance, VCT, adherence support, infection control, and positive prevention. TB services present a readily identifiable cohort for HIV provider-initiated testing. Integrating HAART and DOTS will promote efficient usage of health workers' time and a more navigable experience for patients, ultimately ensuring increased TB treatment completion rates and MDR-TB prevention. As direct observation evolves into a more supportive, empowering experience for patients, adherence to both TB drugs and HAART will be bolstered. Little attention has been paid to the transmission of TB within HIV services. Low cost infection control interventions include: triaging patients, scheduling new and follow-up patients separately; well-ventilated, sheltered waiting rooms; and the use of personal respirators by patients and staff. A more patient-centred approach to TB care may be able to recruit the active participation of TB patients in positive prevention efforts, including maximizing personal infection control, limiting exposure of social contacts to TB during the intensive phase of treatment, advocating isoniazid prophylaxis within the home and patient-centred education efforts to reduce overall transmission. Several model programmes demonstrated synergy, in which the impact of the "whole" or integrated response was greater than the sum of the non-integrated parts.

Summary

The full potential of an integrated TB-HIV service has not been fully harvested. Missed opportunities discount existing efforts in both programmes, will perpetuate the burden of disease, and prevent major gains in future interventions. This paper outlines simple, readily-implementable strategies to narrow the gap and reclaim existing missed opportunities.

Singh and colleagues discuss the threat to regional and global public health posed by XDR-TB in KwaZulu-Natal, and propose new measures to control the outbreak.