Tuberculosis: Poor-Quality Medicines Contribute to Drug Resistance

Background

About a third of the world’s population, concentrated in poorer regions of the world, may be infected with TB, which generally lies dormant until the carrier’s immunity is impaired by another disease (often HIV infection). Without treatment, about half of the patients with active TB will die. According to WHO estimates, TB claimed 1.7 million lives in 2009, most of them in Africa.1 

Standard treatment for TB is long and complicated; it requires that patients take four different antibiotics at different times in different combinations, amounting to fifteen to twenty pills per day over a six-month period. The side-effects of treatment are unpleasant, including fever, vomiting, jaundice, and blurred vision. If treatment is stopped too soon or skipped, the bacteria that are still alive can become resistant to the drugs taken, leading to a form of TB that is much more dangerous and difficult to treat. Drug-resistant strains of TB can quickly become fatal, especially if a patient’s immune system is already compromised. Resistance-driven drug failure is believed to be due largely to patient noncompliance with the drug regimen prescribed. When people start to feel better, they often stop taking the medicine before the TB is completely overwhelmed by the drug. As a result, the still living strain develops resistance to that drug regimen.2 

This problem is not unique to the developing world. The same process is the main reason Western health care systems are plagued by “superbugs.” In poorer locations, though, patient negligence is compounded by irregular supply, stockouts, and inferior medicines that fail even when the patient completes the course of treatment. 

My Research 

Over the past few years my research team has sampled drugs from twenty cities in seventeen countries, and often included the critical first line TB medicines, rifampicin and isoniazid.3  

In some locations, up to 30 percent of TB drugs were substandard: they were underdosed in some way. An aggregate failure rate of 8.25 percent across all samplings shows this is a significant problem. Such a failure rate surely means a portion of the cause of the failure of TB drugs is because patients have taken substandard treatments.

Table below shows the percentage failure of each drug type by whether it was registered by the relevant drug regulatory authority in the country the drug was sold. A drug not-registered does not necessarily mean it is inferior, just that it is technically illegal for it to be sold in the country it was procured from. 

It is not always possible to discern the causes of why a drug is underdosed. It can be because the sample is degraded due to poor storage, or because it has been faked, with some or no active ingredient, but a key problem appears to be substandard products. 

Most of the products that fail in the column marked registered, appear to be fakes with little or no active ingredient. These products are economically damaging to the legitimate company whose product is faked, and more importantly damaging to the patient who takes the drug. But there is a silver lining, if there is no active ingredient then resistance is likely to be unaffected. Also “registered” products fail tests far less often. In most cases the product that failed wasn’t actually registered as it was a fake of a registered product – I cannot be certain of the provenance of every product since some manufacturers refuse to provide information to my research team (the most common response is they provide details of batch numbers etc. only to drug regulators and bulk buying customers).

Far more failures occur in the not-registered products – some of these are fakes with little active ingredient too. But by and large these are products made by real manufacturers, often licensed in at least one country, some of whose products are simply not good enough. Most of the failures in this group (and there are relatively far more of them), would contribute to resistance.

Discussion and Conclusions

The malaria community started paying attention to the dangers of fake and substandard drugs a while ago. Malaria drug experts such as Paul Newton and Nick White, Professors at Oxford University and respectively based in Laos and Thailand most of the time, have written many papers which have successfully alerted the malaria community to the dangers of fake drugs. Less has apparently happened within the TB community.

Perhaps this is understandable – a fake malaria medicine means a child may die in 48 hours, whereas for TB, a fake medicine may not have an immediate or even lasting affect on the patient (if it is just one batch). But while TB is less acutely fatal than malaria, this actually makes the resistance problem of underdosed TB drugs more significant. 

One bad treatment batch, maybe ten underdosed days, may lower the patient's chances of a successful treatment outcome – elimination of the bacteria. It may also extend the required treatment time, increasing both costs and risk of resistance.    

For maybe 10% of cases, Rifampicin and Isoniazid are already lost as treatment options – underdosed drugs will likely increase this percentage.

Recently in Delhi there were apparently cases of TB, which no medicines were able to successfully treat.  Since treatments for MDR/XDR TB are more expensive and less effective than first line treatments, it is absolutely vital to preserve the efficacy of current first line treatments as long as possible. 

At the moment not much attention is paid to this problem by the TB community, and the drug regulatory community is more on watch for bad malaria and HIV drugs than TB drugs, since you haven’t been alerted to the major problems either. 

Most attention is paid to ensuring that low cost TB drugs from India can be accessed by the poor, and this is indeed important. After all interrupted treatment due to inability to pay for drugs may be as damaging as underdosed drugs. But we mustn’t make the two problems antagonistic to each other, we must tackle both of them simultaneously with whatever weapons we have available. While we don’t, and the access arguments trump quality concerns, we may increase patient access to TB drugs only to find out too many of those drugs do not work as anticipated, resulting in a small increase in patient death and a large increase in resistance, with resulting increases in costs and probably longer run fatalities too. 

Excerpt below from forthcoming book “Phake

Rifampicin is a key anti-TB treatment. Fake versions of real rifampicin drugs are readily available in India. Rifa i6 Kid is a children’s treatment for TB, and, unfortunately, there are fake versions of it too. Such a treatment is likely to be administered at home, often without a prescription, which makes detection of fake TB drugs harder. A doctor at a clinic might see enough similar cases to recognize treatment failure due to fake drugs, but a mother has almost no chance. Many mothers choose to treat their children for TB at home because it is less expensive, but they also do it because TB carries a stigma as a poor person’s disease and a mother may be too humiliated to admit her child has TB. In some circles, if a child has TB, society sees it as the mother’s failing and not just a medical problem. The symptoms of TB are well recognized, and most mothers are able to buy familiar brands over the counter. Buying without a prescription is not allowed under Indian law, but my research team’s surveys showed that all of the seventy pharmacies we sampled from in Delhi, Chennai, and Kolkata dispensed medicines without a prescription. 

The Rifa i6 Kid TB treatment sample was procured for me by a private investigator. It  was underdosed, containing about two-thirds of the required API. Given this information, it is not difficult to understand why TB treatment failure continues to grow in the developing world. That people routinely self-treat with drugs of unknown quality makes a mockery of the extremely expensive supervised treatment program recommended by the World Health Organization (WHO) to limit drug resistance.

Aside from the health burden, the financial costs of TB are astounding. The total drug costs for standard treatment, known as first-line treatment, are about $60, reasonable even for the poor in many countries. Second-line treatment for resistant cases (multidrug resistant TB) consists of a bigger range of less-effective drugs with more severe side effects for a period of two years; the treatment costs no less than $15,000.4 

Even if a patient with TB is able to afford such extensive and expensive care, treatment may fail again, resulting in extremely drug-resistant TB (XDR-TB). As the name implies, XDR-TB is effectively untreatable for many patients. In 2006 an outbreak of newly infected XDR-TB was reported in South Africa; that is, patients who had not previously been treated for TB had been infected first by an already extremely resistant strain. Fifty-three patients were admitted to the hospital, and fifty-two died. South Africa is the most affluent country in Africa and had the resources to treat XDR-TB; had the extent of drug resistance been known earlier, fewer lives would have been lost. Even so, subsequent outbreaks in South Africa have claimed the lives of two-thirds of those infected.5  Given a cost of at least $15,000 per patient and treatment requiring hospitalization (preferably in isolation), many diagnostic laboratory tests, access to all available TB drugs, and considerable expertise in TB treatment, it is not surprising that few people are properly treated, even where staffing is available. Generally, patients are kept in isolation and treated with medications that fail most of the time; as a result, most patients infected with XDR-TB die.

Although most TB deaths occur in poor nations, a TB epidemic hit New York City between 1984 and 1994, centered on the poorer immigrant areas, particularly Harlem. Patient compliance was low and drug resistance high; at its peak in 1992, there were 441 cases of multidrug resistant TB. Eventually, the city was able to control the epidemic, but the total cost far exceeded $1 billion.6  At such cost, it is easy to see why few patients in the developing world receive adequate treatment for resistant strains.

All the major killers currently subject to international attention—HIV, malaria, and TB—are infectious diseases caused by pathogens that regularly mutate, thereby protecting themselves from attack by drugs. Moreover, drugs have been counterfeited, falsified, or manufactured so poorly that they do not work for all of these diseases. Substandard drugs can be fatally poisonous or fatally useless, and the enhancement of drug resistance can make effective drugs obsolete, yet the problems of the poor-quality drugs are somehow not serious enough to build political consensus on allocating enough resources to fixing them. Herein lies a major cause of the failure to put an end to the market for dangerous drugs.

Notes

1 Much of this is drawn from my forthcoming book “Phake: The Deadly World of Falsified and Substandard Medicines”, AEI Press/Rowman and Littlefield, April 2012

2 Chan, Margaret. "Tuberculosis." World Health Organization. Last modified November-December 2010. http://www.who.int/mediacentre/factsheets/fs104/en/.

3 See my book Phake for details of methodology, or the following study, which includes some of the drugs described in this talk  - Roger Bate, Richard Tren, Lorraine Mooney, Kimberly Hess, Barun Mitra, Bibek Debroy, and Amir Attaran. “Pilot Study of Essential Drug Quality in Two Major Cities in India.” PLoS One (June 23, 2009), available at http://www.aei.org/article/100667.

4 “Campaign for Access to Essential Medicines,” Medecins Sans Frontieres, March 22, 2011, http://www.msfaccess.org/media-room/press-releases/press-release-detail/?tx_ttnews[tt_news]=1675&cHash=15c0880adb&no_cache=1&print=1; “A 24-Month DR-TB Treatment Regimen Can Cost as Much as US$9,000 for One Patient–470 Times More Than the $19 per Patient It Costs to Cure Standard, Drug-Sensitive TB.”

5 Some South African data can be found here: Jerome Amir Singh, Ross Upshur, and Nesri Padayatchi, "XDR-TB in South Africa: No Time for Denial or Complacency," PLoS Medicine 4 (2007): E50.

6 Richard Coker, “Lessons from New York’s Tuberculosis Epidemic,” British Medical Journal 317 (1998): 616–20.

 

 

 

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