Serological testing versus other strategies for diagnosis of active tuberculosis in India: a cost-effectiveness analysis

Background

Undiagnosed and misdiagnosed tuberculosis (TB) drives the epidemic in India. Serological (antibody detection) TB tests are not recommended by any agency, but widely used in many countries, including the Indian private sector. The cost and impact of using serology compared with other diagnostic techniques is unknown.

Methods and Findings

Taking a patient cohort conservatively equal to the annual number of serological tests done in India (1.5 million adults suspected of having active TB), we used decision analysis to estimate costs and effectiveness of sputum smear microscopy (US$3.62 for two smears), microscopy plus automated liquid culture (mycobacterium growth indicator tube [MGIT], US$20/test), and serological testing (anda-tb ELISA, US$20/test). Data on test accuracy and costs were obtained from published literature. We adopted the perspective of the Indian TB control sector and an analysis frame of 1 year. Our primary outcome was the incremental cost per disability-adjusted life year (DALY) averted. We performed one-way sensitivity analysis on all model parameters, with multiway sensitivity analysis on variables to which the model was most sensitive.If used instead of sputum microscopy, serology generated an estimated 14,000 more TB diagnoses, but also 121,000 more false-positive diagnoses, 102,000 fewer DALYs averted, and 32,000 more secondary TB cases than microscopy, at approximately four times the incremental cost (US$47.5 million versus US$11.9 million). When added to high-quality sputum smears, MGIT culture was estimated to avert 130,000 incremental DALYs at an incremental cost of US$213 per DALY averted. Serology was dominated by (i.e., more costly and less effective than) MGIT culture and remained less economically favorable than sputum smear or TB culture in one-way and multiway sensitivity analyses.

Conclusions

In India, sputum smear microscopy remains the most cost-effective diagnostic test available for active TB; efforts to increase access to quality-assured microscopy should take priority. In areas where high-quality microscopy exists and resources are sufficient, MGIT culture is more cost-effective than serology as an additional diagnostic test for TB. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors'' Summary     

Single cell analysis of antigen-specific T cell responses in HIV-infected individuals

Antigen-specific and polyclonally induced T cell responses were analyzed in 10 HIV-infected individuals and in 14 controls by enumerating the numbers of tetanus toxoid (TT)-specific and phytohemagglutinin (PHA)-induced IFN-gamma-secreting cells (SC) and IL-4-SC using an enzyme-linked immunospot assay. Whereas the numbers of IFN-gamma-SC in HIV-infected patients were not different from those of the controls in response to an in vitro stimulation with PHA, they were significantly decreased in response to an in vitro stimulation with TT, both before and after a TT booster. Cell depletion experiments indicated that this difference was related to an impairment of CD4(+) T-cell-mediated TT-specific IFN-gamma secretion. Concerning IL-4, the numbers of both polyclonally induced IL-4-SC and TT-specific IL-4-SC were significantly lower in HIV-infected patients than in the controls. It is concluded that secretion of antigen-specific cytokines of both Th1 and Th2 types is depressed in HIV-infected patients.     

Ambulatory multi-drug resistant tuberculosis treatment outcomes in a cohort of HIV-infected patients in a slum setting in Mumbai, India

Background

India carries one quarter of the global burden of multi-drug resistant TB (MDR-TB) and has an estimated 2.5 million people living with HIV. Despite this reality, provision of treatment for MDR-TB is extremely limited, particularly for HIV-infected individuals. Médecins Sans Frontières (MSF) has been treating HIV-infected MDR-TB patients in Mumbai since May 2007. This is the first report of treatment outcomes among HIV-infected MDR-TB patients in India.

Methods

HIV-infected patients with suspected MDR-TB were referred to the MSF-clinic by public Antiretroviral Therapy (ART) Centers or by a network of community non-governmental organizations. Patients were initiated on either empiric or individualized second-line TB-treatment as per WHO recommendations. MDR-TB treatment was given on an ambulatory basis and under directly observed therapy using a decentralized network of providers. Patients not already receiving ART were started on treatment within two months of initiating MDR-TB treatment.

Results

Between May 2007 and May 2011, 71 HIV-infected patients were suspected to have MDR-TB, and 58 were initiated on treatment. MDR-TB was confirmed in 45 (78%), of which 18 (40%) were resistant to ofloxacin. Final treatment outcomes were available for 23 patients; 11 (48%) were successfully treated, 4 (17%) died, 6 (26%) defaulted, and 2 (9%) failed treatment. Overall, among 58 patients on treatment, 13 (22%) were successfully treated, 13 (22%) died, 7 (12%) defaulted, two (3%) failed treatment, and 23 (40%) were alive and still on treatment at the end of the observation period. Twenty-six patients (45%) experienced moderate to severe adverse events, requiring modification of the regimen in 12 (20%). Overall, 20 (28%) of the 71 patients with MDR-TB died, including 7 not initiated on treatment.

Conclusions

Despite high fluoroquinolone resistance and extensive prior second-line treatment, encouraging results are being achieved in an ambulatory MDR-T- program in a slum setting in India. Rapid scale-up of both ART and second-line treatment for MDR-TB is needed to ensure survival of co-infected patients and mitigate this growing epidemic.     

Rapid diagnosis of tuberculosis with the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness analysis

Background

Xpert MTB/RIF (Xpert) is a promising new rapid diagnostic technology for tuberculosis (TB) that has characteristics that suggest large-scale roll-out. However, because the test is expensive, there are concerns among TB program managers and policy makers regarding its affordability for low- and middle-income settings.

Methods and Findings

We estimate the impact of the introduction of Xpert on the costs and cost-effectiveness of TB care using decision analytic modelling, comparing the introduction of Xpert to a base case of smear microscopy and clinical diagnosis in India, South Africa, and Uganda. The introduction of Xpert increases TB case finding in all three settings; from 72%–85% to 95%–99% of the cohort of individuals with suspected TB, compared to the base case. Diagnostic costs (including the costs of testing all individuals with suspected TB) also increase: from US$28–US$49 to US$133–US$146 and US$137–US$151 per TB case detected when Xpert is used “in addition to” and “as a replacement of” smear microscopy, respectively. The incremental cost effectiveness ratios (ICERs) for using Xpert “in addition to” smear microscopy, compared to the base case, range from US$41–$110 per disability adjusted life year (DALY) averted. Likewise the ICERS for using Xpert “as a replacement of” smear microscopy range from US$52–$138 per DALY averted. These ICERs are below the World Health Organization (WHO) willingness to pay threshold.

Conclusions

Our results suggest that Xpert is a cost-effective method of TB diagnosis, compared to a base case of smear microscopy and clinical diagnosis of smear-negative TB in low- and middle-income settings where, with its ability to substantially increase case finding, it has important potential for improving TB diagnosis and control. The extent of cost-effectiveness gain to TB programmes from deploying Xpert is primarily dependent on current TB diagnostic practices. Further work is required during scale-up to validate these findings. Please see later in the article for the Editors'' Summary     

Rapid diagnosis of smear-negative tuberculosis using immunology and microbiology with induced sputum in HIV-infected and uninfected individuals

Rationale and Objectives

Blood-based studies have demonstrated the potential of immunological assays to detect tuberculosis. However lung fluid sampling may prove superior as it enables simultaneous microbiological detection of mycobacteria to be performed. Until now this has only been possible using the expensive and invasive technique of broncho-alveolar lavage. We sought to evaluate an immunoassay using non-invasive induced-sputum to diagnose active tuberculosis.

Methods and Results

Prospective cohort study of forty-two spontaneous sputum smear-negative or sputum non-producing adults under investigation for tuberculosis. CD4 lymphocytes specific to purified-protein-derivative of Mycobacterium tuberculosis actively synthesising interferon-gamma were measured by flow cytometry and final diagnosis compared to immunoassay using a cut-off of 0.5%. Sixteen subjects (38%) were HIV-infected (median CD4 count [range] = 332 cells/µl [103–748]). Thirty-eight (90%) were BCG-vaccinated. In 27 subjects diagnosed with active tuberculosis, the median [range] percentage of interferon-gamma synthetic CD4+ lymphocytes was 2.77% [0–23.93%] versus 0% [0–2.10%] in 15 negative for active infection (p<0.0001). Sensitivity and specificity of the immunoassay versus final diagnosis of active tuberculosis were 89% (24 of 27) and 80% (12 of 15) respectively. The 3 positive assays in the latter group occurred in subjects diagnosed with quiescent/latent tuberculosis. Assay performance was unaffected by HIV-status, BCG-vaccination or disease site. Combining this approach with traditional microbiological methods increased the diagnostic yield to 93% (25 of 27) alongside acid-fast bacilli smear and 96% (26 of 27) alongside tuberculosis culture.

Conclusions

These data demonstrate for the first time that a rapid immunological assay to diagnose active tuberculosis can be performed successfully in combination with microbiological methods on a single induced-sputum sample.     

Effectiveness of early antiretroviral therapy initiation to improve survival among HIV-infected adults with tuberculosis: a retrospective cohort study

Background

Randomized clinical trials examining the optimal time to initiate combination antiretroviral therapy (cART) in HIV-infected adults with sputum smear-positive tuberculosis (TB) disease have demonstrated improved survival among those who initiate cART earlier during TB treatment. Since these trials incorporated rigorous diagnostic criteria, it is unclear whether these results are generalizable to the vast majority of HIV-infected patients with TB, for whom standard diagnostic tools are unavailable. We aimed to examine whether early cART initiation improved survival among HIV-infected adults who were diagnosed with TB in a clinical setting.

Methods and Findings

We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with a CD4 count≤350 cells/µl and a TB diagnosis. We estimated the effect of cART on survival using marginal structural models and simulated 2-y survival curves for the cohort under different cART strategies:start cART 15, 30, 60, or 180 d after TB treatment or never start cART. We conducted secondary analyses with composite endpoints of (1) death, default, or lost to follow-up and (2) death, hospitalization, or serious opportunistic infection. Early cART initiation led to a survival benefit that was most marked for individuals with low CD4 counts. For individuals with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15 yielded 2-y survival probabilities of 0.82 (95% confidence interval: [0.76, 0.89]) and 0.86 (95% confidence interval: [0.80, 0.92]), respectively. These were significantly higher than the probabilities computed under later start times. Results were similar for the endpoint of death, hospitalization, or serious opportunistic infection. cART initiation at day 15 versus later times was protective against death, default, or loss to follow-up, regardless of CD4 count. As with any observational study, the validity of these findings assumes that biases from residual confounding by unmeasured factors and from model misspecification are small.

Conclusions

Early cART reduced mortality among individuals with low CD4 counts and improved retention in care, regardless of CD4 count. Please see later in the article for the Editors'' Summary     

Dry-season spawning in a cyprinid fish of southern India

Synopsis A population of the S. Indian cyprinid fishBarbus melanampyx was sampled monthly through 24 months. Seasonal cycles of the gonado-somatic index (GSI), ovarian stages, male breeding tubercles, spawning behaviour and population structure were assessed. These fish breed strictly seasonally during the main dry period: December/January through April. Comparison with other Barbus species of the same general region led to the conclusion that the patterns of reproductive investment ofB. melanampyx are similar to those of perennial species, and different from those of wet-season spawners. The reasons for this rather unexpected result were found in the more constant conditions prevailing during a dry season as compared to the monsoon. It was argued thatB. melanampyx and the species spawning perennially are in effect small-brood spawners, rather than partial spawners.     

Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment

Background

Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.

Methods and Findings

A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6–24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB.Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons.Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).

Conclusion

Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation.     

Determinants of the cost-effectiveness of intermittent preventive treatment for malaria in infants and children

Background

Trials of intermittent preventive treatment in infants (IPTi) and children (IPTc) have shown promising results in reducing malaria episodes but with varying efficacy and cost-effectiveness. The effects of different intervention and setting characteristics are not well known. We simulate the effects of the different target age groups and delivery channels, seasonal or year-round delivery, transmission intensity, seasonality, proportions of malaria fevers treated and drug characteristics.

Methods

We use a dynamic, individual-based simulation model of Plasmodium falciparum malaria epidemiology, antimalarial drug action and case management to simulate DALYs averted and the cost per DALY averted by IPTi and IPTc. IPT cost components were estimated from economic studies alongside trials.

Results

IPTi and IPTc were predicted to be cost-effective in most of the scenarios modelled. The cost-effectiveness is driven by the impact on DALYs, particularly for IPTc, and the low costs, particularly for IPTi which uses the existing delivery strategy, EPI. Cost-effectiveness was predicted to decrease with low transmission, badly timed seasonal delivery in a seasonal setting, short-acting and more expensive drugs, high frequencies of drug resistance and high levels of treatment of malaria fevers. Seasonal delivery was more cost-effective in seasonal settings, and year-round in constant transmission settings. The difference was more pronounced for IPTc than IPTi due to the different proportions of fixed costs and also different assumed drug spacing during the transmission season. The number of DALYs averted was predicted to decrease as a target five-year age-band for IPTc was shifted from children under 5 years into older ages, except at low transmission intensities.

Conclusions

Modelling can extend the information available by predicting impact and cost-effectiveness for scenarios, for outcomes and for multiple strategies where, for practical reasons, trials cannot be carried out. Both IPTi and IPTc are generally cost-effective but could be rendered cost-ineffective by characteristics of the setting, drug or implementation.     

Valproic acid is associated with cognitive decline in HIV-infected individuals: a clinical observational study

Background  

Valproic acid (VPA) is often used to control pain in HIV-related neuropathy. However, the effect of VPA on cognitive functions in advanced HIV-infected individuals is largely unknown. A recent study would suggest that it may have a neuroprotective effect, the doses used were low and the observation period short.     

Interferon-gamma release assays for the diagnosis of active tuberculosis in HIV-infected patients: a systematic review and meta-analysis

Background

Interferon-gamma release assays (IGRAs) have provided a new method for the diagnosis of Mycobacterium tuberculosis infection. However, the role of IGRAs for the diagnosis of active tuberculosis (TB), especially in HIV-infected patients remains unclear.

Methods

We searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001–July 2011 that evaluated the evidence of using QuantiFERON-TB Gold in-tube (QFT-GIT) and T-SPOT.TB (T-SPOT) on blood for the diagnosis of active TB in HIV-infected patients.

Results

The search identified 16 eligible studies that included 2801 HIV-infected individuals (637 culture confirmed TB cases). The pooled sensitivity for the diagnosis of active TB was 76.7% (95%CI, 71.6–80.5%) and 77.4% (95%CI, 71.4–82.6%) for QFT-GIT and T-SPOT, respectively, while the specificity was 76.1% (95%CI, 74.0–78.0%) and 63.1% (95%CI, 57.6–68.3%) after excluding the indeterminate results. Studies conducted in low/middle income countries showed slightly lower sensitivity and specificity when compared to that in high-income countries. The proportion of indeterminate results was as high as 10% (95%CI, 8.8–11.3%) and 13.2% (95%CI, 10.6–16.0%) for QFT-GIT and T-SPOT, respectively.

Conclusion

IGRAs in their current formulations have limited accuracy in diagnosing active TB in HIV-infected patients, and should not be used alone to rule out or rule in active TB cases in HIV-infected patients. Further modification is needed to improve their accuracy.     

Arbuscular mycorrhizas in cycads of southern India

Root and soil samples of three potted or ground-grown cycads ( Cycas circinalis, C. revoluta, Zamiasp.) were collected between November 1999 and June 2000 and surveyed for arbuscular mycorrhizal (AM) colonization and spore populations. AM fungi were associated with all root systems and rhizosphere samples examined. Root colonization was of a typical Arum type and AM colonization levels differed significantly between species and between potted and ground-grown cycads. Mycorrhizal colonization levels were inversely related to root hair number and length. Spores of nine morphotypes belonging to three genera ( Acaulospora, Glomus, Scutellospora) were extracted from soil. The percentage root length colonized by AM fungi was not related to soil factors, but total AM fungal spore numbers in the rhizosphere soil were inversely related to soil nitrogen and phosphorus levels. AM fungal spore numbers in the soil were linearly related to root length colonized. The co-occurrence of septate non-mycorrhizal fungi was recorded for the first time in cycads. These observations and the relationship between plant mycorrhizal status and soil nutrients are discussed.     

Normal immune function of monocyte-derived dendritic cells from HIV-infected individuals: implications for immunotherapy.

Dendritic cells (DC) are the most potent cells involved in the generation of primary and secondary immune responses. To assess the feasibility of using autologous DC as immunotherapy for HIV disease, we analyzed a variety of immune parameters using DC isolated from HIV-infected (HIV+) individuals, as well as DC obtained from HIV-uninfected (HIV-) individuals infected in vitro with HIV. After stimulation with recombinant CD40 ligand (CD40LT), cytokine and beta-chemokine production were similar by DC from HIV- donors infected in vitro with the CCR5-using HIV Ba-L strain (n = 8) compared with uninfected DC from the same donors. Production of beta-chemokines, but not of cytokines, was increased by a CXCR4-using IIIB strain-infected DC (n = 7). Stimulation of HIV-infected DC with CD40LT decreased infection in Ba-L-infected DC, but had no effect on IIIB-infected DC. Consistent with this finding, CD40LT down-regulated CCR5 and up-regulated CXCR4 expression on DC. Monocyte-derived DC were also propagated from 15 HIV+ and 13 HIV- donors. They exhibited similar expression of costimulatory molecules and produced similar amounts of IL-12, IL-10, and beta-chemokines, following stimulation. By contrast, stimulated PBMC from HIV+ patients exhibited decreased IL-12 and increased IL-10 production. In summary, phenotype, cytokine secretion, and beta-chemokine production by DC from HIV+ individuals were normal. These cells may prove useful in boosting cellular immune responses in HIV+ individuals.     

Fine needle aspiration cytology of lymph nodes in HIV-infected individuals

OBJECTIVE: To assess the role of fine needle aspiration cytology (FNAC) in lymphadenopathy in human immunodeficiency virus-infected individuals (HIVII). STUDY DESIGN: Thirty-nine HIVII presenting with lymphadenopathy at University Hospital, Kuala Lumpur, were subjected to FNAC. Cytologic smears were routinely stained with May-Grünwald-Giemsa stain. Special stains and immunostains were used when necessary. RESULTS: In nine cases, the cytologic appearance was compatible with HIV type A and in one case with HIV type C lymphadenopathy. In 21 cases, acid-fast bacilli (AFB) were demonstrated in the cytologic smears, enabling a diagnosis of mycobacterial lymphadenitis. In one of these cases there was a concomitant infection with Penicillium marneffei that was overlooked on initial cytologic examination. The cause of granulomatous lymphadenitis could not be ascertained in one case, where neither AFB nor any other organisms were demonstrable. Two cases of histoplasma and one of cryptococcal lymphadenitis were diagnosed, as was one high grade non-Hodgkin's lymphoma that could be immunophenotyped on cytologic material. In three cases the aspirates were inadequate for a cytologic diagnosis. CONCLUSION: Lymph node FNAC is a valuable investigative modality in HIVII. Most opportunistic infections (bacterial and fungal) can be correctly identified, and high grade lymphoma can be diagnosed and phenotyped.