Striving to provide first-, second- and third-line ARVs

 Life-prolonging antiretroviral (ARV) medication is reaching more HIV-positive Ugandans than ever before, but health workers are concerned about how they will deal with the inevitable rise in drug resistance.

An estimated 400 accredited facilities are providing about 218,000 Ugandans with ARVs, and more than 300,000 have enrolled on HIV treatment, but many patients have died and some have simply abandoned treatment.

Although studies show that ARV adherence is generally high, frequent drug stock-outs as a result of funding shortages and supply-chain problems as well as food insecurity mean that patients have experienced interruptions in their treatment regimens, predisposing them to resistance.

"The … drug resistance problem is in evolution and we need to be prepared to handle it," said Dr Ivan Mambule Kiggundu, study coordinator of the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial which is trying to determine the best option for resource-limited settings at the Infectious Disease Institute (IDI), part of the Mulago Hospital Complex in the capital, Kampala.

Currently, about 3 percent of adults and 4.6 percent of children on ARVs are taking second-line drugs. According to the previous UN World Health Organization (WHO) CD-4 count (which measures immune strength) cut-off of 200, the Ministry of Health has estimated that 379,551 would people require ARVs.

However, Uganda has adopted WHO's new CD-4 cut-off of 350, so the number of people needing treatment will go up significantly - and because more people will be on ARVs for longer, the number of people developing resistance is also likely to rise.

Second-line treatment

Second-line drugs often cost up to four times more than first-line drugs, but so far most patients who need the medicines have access to them. The AIDS Support Organization (TASO) a Ugandan NGO, one of the biggest providers of ARVs in the country, has 32,990 HIV-positive clients, of which 600 are on second line drugs.

The international NGO, Médecins Sans Frontières, has pointed out that the most affordable second-line regimen recommended by WHO costs more than three times the most affordable of the improved first-line regimens recommended by WHO.

Jackie Nankya*, a patient at TASO, developed resistance about five years after starting ARV therapy. "I was adhering to the drugs so well but suddenly the sickness reoccurred with intensity in spite of the drugs," she said.

Nankya suffered from lipodistrophy - the uneven distribution of fats on the body - a common side-effect of some ARVs. She developed a buffalo hump and a large abdomen and lost fat in her legs. Since starting on second-line treatment she is slowly regaining her old shape, but worries about what would happen if she became resistant to the second-line drugs.

''This [lack of funding to ensure sufficient, steady ARV supplies] will result in big numbers of patients failing on the simpler and low-cost first-line drugs and needing more expensive and more sophisticated second-line therapy''

TASO checks the CD4 count and viral load of its clients every 6 months. "When the CD4 count is stagnant and the viral cells are neither decreasing nor reducing then we know they are resistant to the drugs they are taking, if they are adhering," said Carol Asiimwe Mutabazi, a laboratory technician at TASO Kanyanya, on the outskirts of the capital, Kampala.

"Clinically we can also tell that the patients are becoming resistant when in spite of taking ART [antiretroviral treatment] they start getting opportunistic infections like tuberculosis and meningitis."

Third-line treatment

But even organizations as large as TASO do not have the capacity to treat patients who become resistant to second-line drugs. "When a client becomes resistant to the second-line drugs we refer them to the Joint Clinical Research Centre (JCRC)," said Dr Isaiah Kalanzi, TASO’s medical programme officer for the central and south-western regions.

JCRC, Uganda's oldest treatment centre, offers limited access to third-line ARVs. "We have them at JCRC but we do not give them to everybody; we are only giving them to people participating in our research," said Peter Mugyenyi, executive director and founder of JCRC.

The Centre is testing the efficacy of the drugs and drawing up a distribution strategy in a resource- limited setting like Uganda. "We have found that these drugs work very well - they are very important because they will be needed in future," he noted.

Mugyenyi said the need for third-line drugs in Uganda was still small - between 300 and 400 patients nationally - but few of those who could not access the drugs at JCRC would be able to pay the roughly US$3,200 per year for third-line drugs.

Earlier this year, he addressed the US Congress, warning that unless sufficient funding was found for Uganda's ARV programme, treatment interruptions would be inevitable.

In September 2010, the US government stepped in to bridge gaps in Uganda's ARV supply, but significant funding is still required, especially in light of WHO's new treatment guidelines.

"This [lack of funding to ensure sufficient, steady ARV supplies] will result in big numbers of patients failing on the simpler and low-cost first-line drugs, and needing more expensive and more sophisticated second-line therapy," Mugyenyi said. "It would not take long before an increasing number started requiring the ultra-modern, highly expensive third-line drugs - which virtually do not exist in Africa."