M. tuberculosis resistant to the most potent available antibiotics threatens the success of global tuberculosis (TB) control strategies that rely on standard combinations of these drugs . Although resistance to even a single first-line agent can reduce the probability of successful treatment outcome, the most worrisome disease is resistant to both isoniazid and rifampin (multidrug-resistant; MDR). At least 50% of MDR TB patients treated with standard first-line therapy will fail treatment and suffer from relapse, chronic disease, or die . Furthermore, the detection of extensively drug resistant tuberculosis (XDR),[4, 5] defined as MDR with additional resistance to at least a fluoroquinolone and a second-line injectable antibiotic, heightens concern that increasingly resistant forms of tuberculosis will undermine the effectiveness of the current arsenal of treatment .
Determining the burden of MDR TB requires systematic efforts to assess the magnitude and trend of drug-resistant disease. Since 1994, under the leadership of the World Health Organization and the International Union Against Tuberculosis and Lung Diseases (WHO-IUATLD), four Anti-Tuberculosis Resistance in the World reports have been published [1, 7]. These reports include data from countries and regions that conduct either continuous surveillance or periodic surveys for drug resistant disease. The WHO-IUATLD provides guidance for the design of such surveys; the principle requirements are that they 1) include a representative sample of TB cases from the area under study; 2) differentiate between TB cases that have and have not been previously exposed to anti-TB antibiotics; and 3) use standard methods for determining drug resistance and utilize approved reference laboratories for quality assurance .
In some settings, obtaining representative samples of specimens from new and retreatment patients is a challenge. While drug resistance surveys are usually coordinated in the public sector by National Tuberculosis Programs (NTPs), in areas where a substantial fraction of patients are treated by private practitioners, many patients are neither observed in the public sector nor notified to public authorities. Consequently, surveys conducted exclusively on public sector cases may not reflect the local burden of resistance.
Here, we describe a simple mathematical model to investigate potential biases associated with sampling only from public sector cases in India. We use India as our motivating example to examine such biases for two reasons. First, India has the highest burden of TB patients in the world and most patients initially seek care through private practitioners [9, 10]. Second, previous work in India provides information on differences in diagnostic and treatment practices in the public and private sector (each of which are likely to affect the acquisition of drug resistance) and behavioral data suggesting how TB patients move between the private and public sectors . These data are have not been measured and are not generally available for other countries with both a high burden of TB and a sizable private sector in which diagnosis and treatment of TB is common. We present general conditions under which surveys conducted in the public sector provide valid estimates of drug resistance among new, retreatment, and combined cases and suggest methods to test whether these conditions are met. Finally, when exclusion of private sector cases from surveys results in biased estimates of the local burden of resistance, we describe an efficient method for including data from private sector samples to produce valid estimates of resistance.
Private sector providers and drug-resistant tuberculosis in India
India has the largest estimated number of incident (almost 2 million new cases per year) and prevalent TB cases (almost 3.5 million existing cases), representing more than 20% of the total worldwide burden of TB . India has invested heavily in extending free access to high-quality, standardized approaches for diagnosis and directly observed treatment of TB through public sector facilities and since 2006 has offered such services in all districts of the country. Still, surveys indicate that between 50%-90% of Indian patients first seek care through a private practitioner; this preference for care delivered in the private sector exists among patients with major and minor illnesses, patients residing in rural and urban areas, and patients from rich and poor households [9, 10, 13, 14]. Patients may first seek care with for-profit providers despite the fees associated with such services because private sector care is viewed as more accessible and for-profit providers are perceived as more empathic and better able to dispense high quality drugs .
While systematic steps toward improving the quality of TB diagnosis and treatment in the private sector through the WHO Public-Private Mix DOTS model (PPM-DOTS) in India appear promising,[15, 16] most care provided by private practitioners outside of PPM-DOTS programs remains sub-optimal. Specifically, private providers outside of PPM-DOTS do not routinely use sputum smear microscopy to diagnose TB, are more likely to prescribe non-standard regimens of antibiotics, and do not directly observe treatment to ensure adherence [13, 17, 18]. TB patients treated by these private sector providers are thus less likely to complete treatment and, if they survive and are not lost from the health care system entirely, will eventually present for retreatment in either the public or the private sector . TB patients treated with inappropriate drugs or for whom adherence is interrupted also have a higher probability of acquiring drug resistance while on treatment.
Based on eight surveys conducted between 1995 and 2006 that included a total of 3562 patients, 2.8% of new TB patients were estimated to be infected with MDR strains [1, 7]. Only one survey has provided data necessary to estimate the proportion of incident retreatment cases that are drug-resistant; in this 2006 survey of 1047 retreatment cases, 17.4% of cases were infected with MDR strains. Because these drug-resistance surveys are conducted in public sector facilities, it is not clear whether these surveys can be used to infer the level of drug resistance among all TB patients in India. Furthermore, because the risks of successful treatment outcome and acquired drug resistance differ between public and private patients and because patients failing therapy in one sector may switch to the other for retreatment, understanding the relationship between sector-specific treatment outcomes and the patterns in which patients navigate the healthcare system are important for determining biases associated with drug resistance surveys conducted only in the public sector.