Drug-resistant HIV threat looming

HIV-positive patients about to start antiretroviral treatment are warned not to skip even the occasional dose of their medication because of the virus' ability to mutate rapidly and become drug resistant; but what about patients who have never taken treatment and already have a drug-resistant strain of the virus?

In Africa the extent of "primary", or transmitted HIV drug resistance in treatment-naïve (never treated) patients is largely unknown, but a recent study at three clinics in Lusaka, Zambia, found that nearly 6 percent of patients about to start HIV treatment for the first time already had resistance to standard first-line antiretroviral (ARV) drugs.

The study was part of a programme to monitor transmitted HIV drug resistance, as well as "secondary" drug resistance (acquired during treatment), coordinated by the PharmAccess African Studies to Evaluate Resistance (PASER) - a project of the PharmAccess Foundation, a Dutch health NGO - and part of a broader initiative to track HIV drug resistance in Africa and Asia.

PASER and its sister project in Asia - TREAT Asia Studies to Evaluate Resistance (TASER) - share their research findings with the World Health Organization's HIV drug resistance network (HIVResNet) which monitors global trends in HIV drug resistance and advises countries on how to minimize the emergence and transmission of drug-resistant strains of the virus.

PASER has established a network of clinics, laboratories and research centres in six African countries to discover the extent and speed at which HIV drug resistance is spreading. The Zambian study, published in the Journal of AIDS on 1 September, will soon be followed by results from the five other countries.

The lead author, Dr Raph Hamers of the PharmAccess Foundation in Amsterdam, the Netherlands, said preliminary results from the other countries suggested that between 3 and 8 percent of patients who were yet to start treatment had "baseline" resistance to first-line ARVs.

In Europe and the United States, where ARV treatment became available years earlier than in Africa, up to 20 percent of new HIV patients have drug resistance. "We are all worried that we will reach similar levels in Africa," said Hamers, adding that treatment programmes on the continent were much less regulated than Western ones, and more prone to drug supply interruptions.

Shortages of staff and resources meant treatment programmes in Africa are also often ill-equipped to pick up on patients who are failing treatment and developing drug resistance - such patients can transmit drug-resistant strains to their sexual partners and children.

I understand we have a million people on treatment, but if we don't think about the next 20 years, it'll be like the problem we have now with drug-resistant TB

"Imagine if one out of four [HIV-positive] people in Africa were infected with [drug] resistant viruses, and needed to immediately start second- and third-line treatment," said Prof Tobias Rinke de Wit, programme director of PASER.

With budgets for HIV/AIDS treatment already shrinking as a result of the global economic crisis, and second-line ARVs costing at least five times more than first-line drugs, such a scenario could stall efforts to expand treatment access. Even worse, it could lead to the development of strains of HIV resistant to multiple classes of ARVs, making them virtually untreatable.

Dr Theresa Rossouw, an HIV clinician, estimates that between 5 and 10 percent of the new patients she sees at clinics in the Pretoria area of South Africa have drug resistance. "I understand we have a million people on treatment," she said, referring to South Africa's national ARV treatment programme. "But if we don't think about the next 20 years, it'll be like the problem we have now with drug-resistant TB."

Lack of drug-resistance testing

Part of the difficulty of monitoring the spread of primary HIV drug resistance is detecting it in individuals who are not yet enrolled in a programme or subject to routine monitoring. WHO advises countries to develop surveillance systems that regularly measure HIV drug resistance in a sample of untreated patients.

Even for patients who are enrolled in care, drug resistance testing in Africa is either unavailable or prohibitively expensive. If a patient is failing treatment, doctors mainly rely on viral load (a measure of the amount of HI virus in the blood) and CD4 count testing (a measure of immune system strength) to determine whether they need to be switched to second-line drugs. In some African countries the availability of viral load is very limited, and patients are kept on first-line treatment long after it becomes ineffective.

PASER is trying to address this problem with its Affordable Resistance Test for Africa (ART-A) - a cheaper, easier-to-use test that analyses dried blood spots for HIV drug resistance - being piloted in Uganda and South Africa. "By the end of this year we'll know how the test is performing in the field, then ... you have to take it from the lab into a product, and that ... could take one to two years," said Rinke de Wit.

The new test would still be too expensive to use for every HIV patient. "Resistance testing should only be done when people are already failing [treatment]," he said. "As budgets are going down for ARVs, it wouldn't be responsible to do [it] more widely."

Nevertheless, a point-of-care drug resistance test would make "a huge difference", Rossouw said. "We can prevent about a third of patients going onto second-line therapy by having this test that could pick up on resistance from an early stage."

Doing drug-resistance testing every six months might be more cost-effective than some of the other routine monitoring, such as CD4 count testing, she told IRIN/PlusNews.

Risks of monotherapy

Rossouw said the need for programmes like PASER's was particularly vital in light of the common use of single-dose nevirapine to prevent mother-to-child HIV transmission (PMTCT) in Africa. Mono- and even dual ARV therapy often led to the development of drug resistance, although some research has suggested that such resistance wanes over time.

In the Zambian study, most patients with primary drug resistance had resistance to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), which includes nevirapine as well as efavirenz - both widely used in Africa in first-line ARV regimens.

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The difference in the number of men and women with drug resistance in the study was not significant. "Either single-dose nevirapine is not significant, or you could argue that females transmit their drug-resistant virus to males," Hamers said, adding that more studies were needed before local policy-makers considered changing the drugs in their national treatment and PMTCT programmes.

Rossouw argued that African treatment programmes should start using ARVs more responsibly to avoid major problems in the not-too-distant future. "We've been in a type of honeymoon period with ARVs, but as we have patients that are more treatment-experienced - like they've seen in the Zambian cohort - the individual patient won't respond as well to treatment," she pointed out.

"I definitely think we're going to end up with primary resistance, like we've seen in the [United] States, of about 15 to 20 percent."

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