The majority of patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are co-infected with HIV, but the radiographic features of MDR-TB and their relationship with time to sputum culture conversion in the antiretroviral therapy era have not been described.
We reviewed baseline chest radiographs for 56 patients with MDR-TB from a rural area of South Africa. We analyzed the association of cavities, consolidation, pleural effusion and hilar lymphadenopathy with time to sputum culture conversion, adjusting for HIV status, baseline sputum smear and CD4 count.
Of the 56 subjects, 49 (88%) were HIV-positive, with a median CD4 count of 136 cells/mm3 (IQR 65-249). Thirty-two (57%) patients were sputum smear positive. Twenty-two (39%) patients had a cavity and 37 (66%) patients had consolidations. Cavitary disease and consolidations were each associated with longer time to culture conversion on bivariate analysis but not after adjusting for sputum smear status (aORs 1.79 [0.94-3.42] and 1.09 [0.67-1.78], respectively). Positive baseline sputum smear remained independently associated with longer time to conversion (aOR 3.45 [1.39-8.59]). We found no association between pleural effusion or hilar lymphadenopathy and time to conversion. Seventy-nine percent of patients were cured at the end of treatment.
Despite high rates of HIV co-infection and advanced immunodeficiency, the majority of patients had severe pathology on baseline chest radiograph. Nevertheless, culture conversion rates were high and treatment outcomes were favorable. Cavitation and consolidation do not appear to have an independent association with time to culture conversion beyond that of baseline sputum smear status.
Concerns about immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during anti-tuberculosis treatment in co-infected patients.
We assessed IRIS incidence, severity, and outcomes relative to timing of ART initiation in patients with HIV-related tuberculosis (HIV-TB).
An outpatient clinic in Durban, South Africa
642 HIV-TB co-infected patients
In a secondary analysis of the SAPiT trial, IRIS was assessed in patients randomized to initiate ART either within four weeks of tuberculosis treatment initiation (early integrated-treatment arm), within four weeks of completion of the intensive phase of tuberculosis treatment (late integrated-treatment arm) or within four weeks after tuberculosis therapy completion (sequential-treatment arm). IRIS was defined as new onset or worsening symptoms, signs or radiographic manifestations temporally related to treatment initiation accompanied by a treatment response. IRIS severity, hospitalization and time to resolution were monitored.
IRIS incidence was 19.5 (n=43), 7.5 (n=18) and 8.1 (n=19) per 100 person-years in the early integrated-, late integrated-, and sequential-treatment arms, respectively; P < 0.001, and 45.5, 9.7 and 19.7 per 100 person-years in patients with baseline CD4+ counts <50 cells/mm3, P = 0.004. IRIS incidence was higher in the early integrated- compared to the late integrated- (incidence rate ratio (IRR) = 2.6, 95%confidence interval (CI): 1.5 to 4.8; P < 0.001) or sequential-treatment arm (IRR=2.4, 95%CI: 1.4 to 4.4; P < 0.001). IRIS cases in the early integrated-treatment arm were more severe (34.9% vs. 18.9%, P = 0.18); had significantly higher hospitalization rates (18/43 vs. 5/37; P = 0.01), and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) compared to IRIS cases in the other two arms.
IRIS could not be assessed, due to LTFU, withdrawal or death within 6 months of scheduled ART initiation, in more patients from the sequential treatment arm (n=74) than in the late integrated treatment arm (n=50) and in the early integrated treatment arm (n=32). This study did not assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis.
Initiation of ART early during tuberculosis treatment resulted in significantly higher IRIS rates, with longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings, particularly relevant to patients initiating ART with CD4+ counts < 50 cells/mm3, need to be considered together with the increased survival benefit of early ART initiation in this group. Clintrials.gov: NCT00398996
Extensively drug-resistant (XDR) tuberculosis has spread among hospitalized patients in South Africa, but the epidemic-level impact of hospital-based infection control strategies remains unknown.
We investigated the effect of administrative, environmental, and personal infection control measures on the epidemic trajectory of XDR tuberculosis in a rural South African community. Assessments were performed with a mathematical model, which incorporated inpatient airborne tuberculosis transmission and community tuberculosis and HIV transmission.
If no new interventions are introduced, 1,300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012. Over half of these cases are likely to be nosocomially transmitted. Mask use would avert less than 10% of overall cases, due to long inpatient exposure times and real-world face-seal leakage rates, but could reduce a significant proportion of hospital staff XDR tuberculosis cases. Combining mask use with reduced hospitalization time and a shift to outpatient therapy, however, could prevent nearly one-third of XDR tuberculosis cases. Supplementing this approach with improved ventilation, rapid drug resistance testing, HIV treatment, and tuberculosis isolation facilities could avert 48% of XDR tuberculosis cases (range 34-50%) by the end of 2012. Involuntary detention, however, could result in an unexpected rise in incidence, given limited isolation capacity.
In the face of rising XDR tuberculosis incidence, prevalence and burden on the health care system, a synergistic combination of available nosocomial infection control strategies may prevent nearly half of XDR tuberculosis cases, even in a resource-limited setting. XDR tuberculosis transmission will continue in the community in spite of such efforts, however, indicating the need to develop parallel community-based programs.
Tuberculosis, Drug-Resistant; Tuberculosis, Multidrug-Resistant; Tuberculosis, Extensively Drug-Resistant; Tuberculosis, MDR; Tuberculosis, XDR; Mathematical Model; Nosocomial Infections; Hospital Infections; South Africa; Infection Control
Transmission of drug susceptible and drug resistant TB occurs in health care facilities, and community and households settings, particularly in highly prevalent TB and HIV areas. There is a paucity of data regarding factors that may affect TB transmission risk in household settings. We evaluated air exchange and the impact of natural ventilation on estimated TB transmission risk in traditional Zulu homes in rural South Africa.
We utilized a carbon dioxide decay technique to measure ventilation in air changes per hour (ACH). We evaluated predominant home types to determine factors affecting ACH and used the Wells-Riley equation to estimate TB transmission risk.
Two hundred eighteen ventilation measurements were taken in 24 traditional homes. All had low ventilation at baseline when windows were closed (mean ACH = 3, SD = 3.0), with estimated TB transmission risk of 55.4% over a ten hour period of exposure to an infectious TB patient. There was significant improvement with opening windows and door, reaching a mean ACH of 20 (SD = 13.1, p < 0.0001) resulting in significant decrease in estimated TB transmission risk to 9.6% (p < 0.0001). Multivariate analysis identified factors predicting ACH, including ventilation conditions (windows/doors open) and window to volume ratio. Expanding ventilation increased the odds of achieving ≥12 ACH by 60-fold.
There is high estimated risk of TB transmission in traditional homes of infectious TB patients in rural South Africa. Improving natural ventilation may decrease household TB transmission risk and, combined with other strategies, may enhance TB control efforts.
Tuberculosis transmission; MDR/XDR TB; Household; South Africa; Infection control; Ventilation
The optimal approach to HIV-associated KS (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes.
We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naïve patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine and nevirapine (Triomune®); CXT arm received Triomune® plus bleomycin, doxorubicin, and vincristine (ABV) every 3 weeks. When ABV was not available, oral etoposide (50-100 mg days 1-21 of a 28 day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included: time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence and quality-of-life.
59 subjects were randomized to HAART, 53 to CXT. 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference 27%; 95% CI 9%-43%, p=0.005). At 12 months, 77% were alive (no survival difference between arms, p=0.49), 82% had HIV viral load <50 copies/mL without difference between arms, (p=0.47); CD4 counts and QOL measures improved in all patients.
HAART with chemotherapy produced higher overall KS response over 12 months, while HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and HHV-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.
Kaposi sarcoma; acquired immunodeficiency syndrome; human immunodeficiency virus; highly active antiretroviral therapy; South Africa
As the South African province of KwaZulu-Natal addresses a growing multidrug-resistant tuberculosis (MDR-TB) epidemic by shifting care and treatment from trained specialty centers to community hospitals, delivering and monitoring MDR-TB therapy has presented new challenges. In particular, tracking and reporting adverse clinical events have been difficult for mobile healthcare workers (HCWs), trained health professionals who travel daily to patient homes to administer and monitor therapy. We designed and piloted a mobile phone application (Mobilize) for mobile HCWs that electronically standardized the recording and tracking of MDR-TB patients on low-cost, functional phones.
We assess the acceptability and feasibility of using Mobilize to record and submit adverse events forms weekly during the intensive phase of MDR-TB therapy and evaluate mobile HCW perceptions throughout the pilot period.
All five mobile HCWs at one site were trained and provided with phones. Utilizing a mixed-methods evaluation, mobile HCWs’ usage patterns were tracked electronically for seven months and analyzed. Qualitative focus groups and questionnaires were designed to understand the impact of mobile phone technology on the work environment.
Mobile HCWs submitted nine of 33 (27%) expected adverse events forms, conflicting with qualitative results in which mobile HCWs stated that Mobilize improved adverse events communication, helped their daily workflow, and could be successfully expanded to other health interventions. When presented with the conflict between their expressed views and actual practice, mobile HCWs cited forgetfulness and believed patients should take more responsibility for their own care.
This pilot experience demonstrated poor uptake by HCWs despite positive responses to using mHealth. Though our results should be interpreted cautiously because of the small number of mobile HCWs and MDR-TB patients in this study, we recommend carefully exploring the motivations of HCWs and technologic enhancements prior to scaling new mHealth initiatives in resource poor settings.
There is little information regarding the presence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA), an important nosocomial pathogen, in rural African hospitals.
To determine the prevalence of MRSA colonisation in patients admitted to a rural hospital with tuberculosis (TB) in an endemic HIV area and to describe transmission dynamics and resistance patterns among MRSA isolates.
A prospective prevalence survey in the adult TB wards of the Church of Scotland Hospital, a provincial government district hospital in Tugela Ferry, KwaZulu-Natal. Patients were eligible if over the age of 15 and admitted to the TB wards between 15 November and 15 December 2008. Nasal swabs were cultured within 24 hours of admission and repeated at hospital-day 14 or upon discharge. Susceptibility testing was performed with standard disk diffusion. Demographic and clinical information was extracted from medical charts.
Of 52 patients with an admission nasal swab, 11 (21%) were positive for MRSA. An additional 4 (10%) of patients with negative admission swabs were positive for MRSA on repeat testing. MRSA carriage on admission was more common among patients with previous hospitalisation, and among HIV-infected patients was significantly associated with lower CD4 counts (p=0.03). All MRSA isolates were resistant to cotrimoxazole, and 74% were resistant to ≥5 classes of antibiotics; all retained susceptibility to vancomycin.
A high prevalence of multidrug-resistant MRSA nasal carriage was found. Studies are needed to validate nosocomial acquisition and to evaluate the impact of MRSA on morbidity and mortality among TB patients in similar settings.
Treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) in South Africa have suffered as centralized, inpatient treatment programs struggle to cope with rising prevalence and HIV co-infection rates. A new treatment model is needed to expand treatment capacity and improve MDR-TB and HIV outcomes. We describe the design and preliminary results of an integrated, home-based MDR-TB/HIV treatment program created in rural KwaZulu-Natal. In 2008, a decentralized center was established to provide outpatient MDR-TB and HIV treatment. Nurses, community health workers, and family supporters have been trained to administer injections, provide adherence support, and monitor adverse reactions in patients’ homes. Physicians assess clinical response, adherence, and adverse reaction severity to MDR-TB and HIV therapy at monthly follow-up visits. Treatment outcomes are assessed by monthly cultures and CD4 and viral load every 6 months. Eighty patients initiated MDR-TB therapy from 2/2008–4/2010; 66 were HIV co-infected. Retention has been high (only 5% defaults, 93% of visits attended) and preliminary outcomes have been favorable (77% cured/still on treatment, 82% undetectable viral load). Few patients have required escalation of care (9%), had severe adverse events (8%), or died (6%). Integrated, home-based treatment for MDR-TB and HIV is a promising treatment model to expand capacity and achieve improved outcomes in rural, resource-poor, and high-HIV prevalent settings.
HIV/AIDS; Multidrug-resistant tuberculosis; Community-based treatment; Program development; AIDS
This series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication.
Opioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-hour blood sampling studies: 1. for buprenorphine pharmacokinetics and 2. following 15 days of rifampin 600 mg daily or rifabutin 300 mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics.
Rifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p=<0·001) and onset of opiate withdrawal symptoms in 50% of participants (p=0·02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p<0·001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p=0·009), although rifabutin and its active metabolite concentrations remained in the therapeutic range.
Rifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed.
buprenorphine/naloxone; rifampin; rifabutin; tuberculosis; opioid addiction; drug interactions
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
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.
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).
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.
Drug-resistant tuberculosis (TB) is a major threat to global public health. Patients with extensively drug-resistant TB (XDR-TB), particularly those with HIV-coinfection, experience high and accelerated mortality with limited available interventions. To determine modifiable factors associated with survival, we evaluated XDR-TB patients from a community-based hospital in rural South Africa where a large number of XDR-TB cases were first detected.
A retrospective case control study was conducted of XDR-TB patients diagnosed from 2005–2008. Survivors, those alive at 180 days from diagnostic sputum collection date, were compared with controls who died within 180 days. Clinical, laboratory and microbiological correlates of survival were assessed in 69 survivors (median survival 565 days [IQR 384–774] and 73 non-survivors (median survival 34 days [IQR 18–90]). Among 129 HIV+ patients, multivariate analyses of modifiable factors demonstrated that negative AFB smear (AOR 8.4, CI 1.84–38.21), a lower laboratory index of routine laboratory findings (AOR 0.48, CI 0.22–1.02), CD4>200 cells/mm3 (AOR 11.53, 1.1–119.32), and receipt of antiretroviral therapy (AOR 20.9, CI 1.16–376.83) were independently associated with survival from XDR-TB.
Survival from XDR-TB with HIV-coinfection is associated with less advanced stages of both diseases at time of diagnosis, absence of laboratory markers indicative of multiorgan dysfunction, and provision of antiretroviral therapy. Survival can be increased by addressing these modifiable risk factors through policy changes and improved clinical management. Health planners and clinicians should develop programmes focusing on earlier case finding and integration of HIV and drug-resistant TB diagnostic, therapeutic, and preventive activities.
Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
buprenorphine/naloxone; atazanavir; ritonavir; drug interactions
In 2005 a cluster of 53 HIV-infected patients with extensively drug-resistant tuberculosis (XDR-TB) was detected in the Msinga sub-district, the catchment area for the Church of Scotland Hospital (CoSH) in Tugela Ferry, in KwaZulu-Natal province (KZN), South Africa. KZN is divided into 11 healthcare districts. We sought to determine the distribution of XDR TB cases in the province in relation to population density.
In this cross-sectional study, the KZN tuberculosis laboratory database was analysed. Results of all patients with a sputum culture positive for Mycobacterium tuberculosis from January 2006 to June 2007 were included. Drug-susceptibility test results for isoniazid, rifampicin, ethambutol, streptomycin, kanamycin and ofloxacin were available for all patients as well as the location of the hospital where their clinical diagnosis was made.
In total, 20858 patients attending one of 73 hospitals or their adjacent clinics had cultures positive for M. tuberculosis. Of these, 4170 (20%) were MDR-TB cases. Four hundred and forty three (11%) of the MDR tuberculosis cases displayed the XDR tuberculosis susceptibility profile. Only 1429 (34%) of the MDR-TB patients were seen at the provincial referral hospital for treatment. The proportion of XDR-TB amongst culture-confirmed cases was highest in the Msinga sub-district (19.6%), followed by the remaining part of the Umzinyati district (5.9%) and the other 10 districts (1.1%). The number of hospitals with at least one XDR-TB case increased from 18 (25%) to 58 (80%) during the study period.
XDR-TB is present throughout KZN. More than 65% of all diagnosed MDR-TB cases, including XDR-TB patients, were left untreated and likely remained in the community as a source of infection.
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.
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.
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.
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.
We expanded second-line tuberculosis (TB) drug susceptibility testing for extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa. Of 19 patients with extensively drug-resistant TB identified during February 2008–April 2009, 13 (68%) had isolates resistant to all 8 drugs tested. This resistance leaves no effective treatment with available drugs in South Africa.
Extensively drug-resistant tuberculosis; tuberculosis and other mycobacteria; HIV; drug resistance; second-line drugs; South Africa; dispatch
To assess the association between adherence to antiretroviral therapy and the presence of class-specific antiretroviral medication resistance.
Secondary analysis of prospective clinical trial data
Participants randomized to the protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) strategies of the Community Programs for Clinical Research on AIDS (CPCRA) Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study were included. Adherence was measured by 7-day self-report. Virological failure was defined as an HIV-RNA > 1000 at or after 4 months. The association between cumulative adherence and the development of class-specific genotypic resistance was assessed by Cox regression analysis.
Included were 457 and 446 antiretroviral naïve participants on the PI and NNRTI strategies respectively. The median time to initial virological failure in the PI strategy was 1.2 years; 135 (30%) individuals failed with resistance. The median time to initial virological failure in the NNRTI strategy was 3.0 years; 127 (28%) failed with resistance. No association was found between cumulative adherence and PI resistance (HR 1.1, 95% CI 0.9 – 1.4 per 10% lower adherence). However, lower cumulative adherence was associated with an increased risk of NNRTI resistance at initial virological failure (HR 1.2, 95% CI 1.1 – 1.3 per 10% lower adherence). In both strategies lower cumulative adherence was associated with an increased risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance at initial virological failure.
Adherence-resistance relationships are class-specific. For NRTIs and NNRTIs, initial virological failure with resistance is more likely at lower levels of cumulative adherence.
adherence; antiretroviral therapy; HIV; virological failure; antiretroviral resistance
Comprehensive and successful tuberculosis (TB) care and treatment must incorporate effective airborne infection-control strategies. This is particularly and critically important for health care workers and all persons with or at risk of human immunodeficiency virus (HIV) infection. Past and current outbreaks and epidemics of drug-susceptible, multidrug-resistant, and extensively drug-resistant TB have been fueled by HIV infection, with high rates of morbidity and mortality and linked to the absence or limited application of airborne infection-control strategies in both resource-rich and resource-limited settings. Airborne infection-control strategies are available—grouped into administrative, environmental, and personal protection categories—and have been shown to be associated with decreases in nosocomial transmission of TB; their efficacy has not been fully demonstrated, and their implementation is extremely limited, particularly in resource-limited settings. New research and resources are required to fully realize the potential benefits of infection control in the era of TB and HIV epidemics.
Little is known about the time to sputum culture conversion in MDR-TB patients co-infected with HIV, although such patients have, historically, had poor outcomes. We describe culture conversion rates among MDR-TB patients with and without HIV-co-infection in a TB-endemic, high-HIV prevalent, resource-limited setting.
Patients with culture-proven MDR-TB were treated with a standardized second-line regimen. Sputum cultures were taken monthly and conversion was defined as two negative cultures taken at least one month apart. Time-to-conversion was measured from the day of initiation of MDR-TB therapy. Subjects with HIV received antiretroviral therapy (ART) regardless of CD4 count.
Among 45 MDR-TB patients, 36 (80%) were HIV-co-infected. Overall, 40 (89%) of the 45 patients culture-converted within the first six months and there was no difference in the proportion who converted based on HIV status. Median time-to-conversion was 62 days (IQR 48-111). Among the five patients who did not culture convert, three died, one was transferred to another facility, and one refused further treatment before completing 6 months of therapy. Thus, no patients remained persistently culture-positive at 6 months of therapy.
With concurrent second-line TB and ART medications, MDR-TB/HIV co-infected patients can achieve culture conversion rates and times similar to those reported from HIV-negative patients worldwide. Future studies are needed to examine whether similar cure rates are achieved at the end of MDR-TB treatment and to determine the optimal use and timing of ART in the setting of MDR-TB treatment.
The presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control.
XDR TB; multiple-drug-resistant tuberculosis (MDR TB); TB/HIV coinfection; Tugela Ferry; South Africa
Purpose of review
Physicians, researchers and policy makers must understand the myriad consequences of multidrug and extensively drug-resistant tuberculosis (TB) within the HIV community in order to guide clinical care, research and resource allocation.
Extensively drug-resistant TB can no longer be considered as occurring in isolated outbreaks as it has been reported in 45 countries from all regions of the world. HIV has been associated as an independent risk factor for infection with drug-resistant TB. HIV patients appear more likely to suffer from primary, transmitted resistance as opposed to developing acquired resistance during the course of treatment for TB. New rapid diagnostics offer promise of providing clinically useful first-line drug susceptibility information but require validation in HIV patients and smear negative individuals. Demonstration projects of community-based treatment of drug-resistant TB and integration of TB and HIV care provide opportunities to decentralize management of drug-resistant TB.
Multidrug-resistant and extensively drug-resistant TB disproportionately affect HIV patients and result in increased morbidity and mortality. In this study, we address these challenging issues and offer some short-term and longer term strategies for their alleviation.
drug-resistant tuberculosis; extensively drug-resistant tuberculosis; multidrug-resistant tuberculosis; South Africa; tuberculosis/HIV coinfection
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings, which generally lack laboratory infrastructure for diagnosing TB drug resistance. Even where available, inherent delays with current drug-susceptibility testing (DST) methods result in clinical deterioration and ongoing transmission of MDR and XDR-TB. Identifying clinical predictors of drug resistance may aid in risk stratification for earlier treatment and infection control.
We performed a retrospective case-control study of patients with MDR (cases), XDR (cases) and drug-susceptible (controls) TB in a high-HIV-prevalence setting in South Africa to identify clinical and demographic risk factors for drug-resistant TB. Controls were selected in a 1∶1∶1 ratio and were not matched. We calculated odds ratios (OR) and performed multivariate logistic regression to identify independent predictors.
We enrolled 116, 123 and 139 patients with drug-susceptible, MDR, and XDR-TB. More than 85% in all three patient groups were HIV-infected. In multivariate analysis, MDR and XDR-TB were each strongly associated with history of TB treatment failure (adjusted OR 51.7 [CI 6.6-403.7] and 51.5 [CI 6.4–414.0], respectively) and hospitalization more than 14 days (aOR 3.8 [CI 1.1–13.3] and 6.1 [CI 1.8–21.0], respectively). Prior default from TB treatment was not a risk factor for MDR or XDR-TB. HIV was a risk factor for XDR (aOR 8.2, CI 1.3–52.6), but not MDR-TB. Comparing XDR with MDR-TB patients, the only significant risk factor for XDR-TB was HIV infection (aOR 5.3, CI 1.0–27.6).
In this high-HIV-prevalence and drug-resistant TB setting, a history of prolonged hospitalization and previous TB treatment failure were strong risk factors for both MDR and XDR-TB. Given high mortality observed among patients with HIV and drug-resistant TB co-infection, previously treated and hospitalized patients should be considered for empiric second-line TB therapy while awaiting confirmatory DST results in settings with a high-burden of MDR/XDR-TB.
The yield of mycobacterial blood cultures for multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) among drug-resistant TB suspects has not been described.
We performed a retrospective, cross-sectional analysis to determine the yield of mycobacterial blood cultures for MDR-TB and XDR-TB among patients suspected of drug-resistant TB from rural South Africa. Secondary outcomes included risk factors of Mycobacterium tuberculosis bacteremia and the additive yield of mycobacterial blood cultures compared to sputum culture.
From 9/1/2006 to 12/31/2008, 130 patients suspected of drug-resistant TB were evaluated with mycobacterial blood culture. Each patient had a single mycobacterial blood culture with 41 (32%) positive for M. tuberculosis, of which 20 (49%) were XDR-TB and 8 (20%) were MDR-TB. One hundred fourteen (88%) patients were known to be HIV-infected. Patients on antiretroviral therapy were significantly less likely to have a positive blood culture for M. tuberculosis (p = 0.002). The diagnosis of MDR or XDR-TB was made by blood culture alone in 12 patients.
Mycobacterial blood cultures provided an additive yield for diagnosis of drug-resistant TB in patients with HIV from rural South Africa. The use of mycobacterial blood cultures should be considered in all patients suspected of drug-resistant TB in similar settings.
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 AUC0-24h and Cmax were 43.9 ng▪hr/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (≥7 days), these values were similar at 43.7 ng▪hr/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC0-24h [68.7 to 14.7 ng▪hr/mL; ratio=0.21 (90% CI 0.19–0.25)] and Cmax [4.75 to 0.94 ng/mL; ratio=0.20 (90% CI 0.17–0.23)]. The last measurable NLX concentration (Clast) 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 AUC0-12h and Cmax decreased 19% and 25% respectively, and Cmin 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.
pharmacotherapy; HIV/AIDS; pharmacokinetics; antiviral treatment; maintenance; opiates
Extensively drug-resistant tuberculosis; HIV; lymphadenitis; tuberculous; pleurisy; tuberculous; bacteria; South Africa; CME; dispatch
Evaluate the feasibility, fidelity, and effectiveness of an HIV prevention intervention delivered to HIV-infected patients by counselors during routine clinical care in KwaZulu-Natal, South Africa.
Total of 152 HIV-infected patients, aged 18 years and older, receiving clinical care at an urban hospital in South Africa, were randomly assigned to intervention or standard-of-care control counselors. Intervention counselors implemented a brief risk reduction intervention at each clinical encounter to help patients reduce their unprotected sexual behavior. Self-report questionnaires were administered at baseline and 6 months to assess number of unprotected sex events in previous 3 months.
Intervention was delivered in 99% of routine patient visits, and included a modal 8 of 8 intervention steps. Although HIV-infected patients in both conditions reported more vaginal and anal sex events at 6-month follow-up than at baseline, patients who received the counselor-delivered intervention reported a significant decrease over time in number of unprotected sexual events. There was a marginally significant increase in these events among patients in the standard-of-care control condition.
A counselor-delivered HIV prevention intervention targeting HIV-infected patients appears to be feasible to implement with fidelity in the South African clinical care setting and effective at reducing unprotected sexual behavior.
HIV prevention intervention; PLWHA; counselor-delivered; South Africa; IMB model; HIV clinical care