Racing to keep resistant HIV at bay

The sustainability of the national HIV treatment programme in Botswana, and elsewhere in Africa, depends on avoiding widespread drug resistance that could threaten long-term affordability. Patients who miss even five percent of their drug doses can develop resistant strains of the virus, and will need to switch to second-line medication at more than double the cost. Botswana was the first country in Africa to implement a nationwide antiretroviral (ARV) programme. Four years later, 85 percent of patients, including those using the private sector, are receiving treatment, and the programme has often been held up as a test case for the rest of the continent. Other countries in the region lag far behind - while they are focusing on a wider distribution of ARVs, Botswana's major challenge is to ensure that patients stick to their daily regimen. When Botswana began enrolling patients for treatment in 2002, the question of whether such a programme could succeed outside the developed world was still unanswered. Some of the concerns were whether people living in resource-poor settings would have the necessary education levels to grasp the importance of taking a complex combination of drugs every day for the rest of their lives, or the economic means to access proper nutrition and transport to and from clinics. These concerns have turned out to be largely unfounded. In a study on treatment adherence and drug resistance, researchers at the Botswana-Harvard AIDS Institute found little evidence of treatment fatigue - becoming less vigilant about taking the pills over time - and patients have so far demonstrated better or at least the equivalent adherence of their western counterparts. "People here are very committed to getting well," said Hermann Bussmann, one of the researchers. "They know the importance of not missing doses." The study compares the effectiveness of two drug adherence strategies: the standard approach of Botswana's National AIDS Coordinating Agency, which matches patients with a 'buddy' who supports and encourages them to take their medication on time; and directly observed treatment (DOT), already used with TB patients, in which community health workers supervise patients while they take their medication. The results will not be available for at least another year, but according to Dr Ava Avalos, part of a team at the Infectious Diseases Care Clinic (IDCC) at Princess Marina Hospital in Gaborone that monitors and manages patients with treatment failure, only four percent of the clinic's 14,000 patients have had to be switched to second or third-line regimens. "We're doing much better than anyone had anticipated," Avalos said. "At this clinic we really bombard patients with information and adherence counselling services. Because we're a specialised HIV clinic we can do that, but not every rollout clinic can." Data on whether other clinics in the country or the continent have similarly low levels of first-line treatment failure are not yet available. According to Dr. Jos Perriens, of the AIDS Medicines and Diagnostics Service at the World Health Organisation (WHO), second-line drugs comprised only 1.5 percent of total ARV procurement by low- and middle-income countries last year. This did not necessarily reflect the real incidence of treatment failure, he added, and could also be the result of difficulty in procuring or affording second-line drugs. Medecins Sans Frontieres (MSF), the international humanitarian medical aid agency, has warned that unless drug manufacturers and regulatory authorities start fast-tracking the availability of second-line drugs in Africa, and significantly lowering the cost, a crisis could occur when large numbers of patients start developing resistance to first-line treatment in a few years' time. Avalos conceded that accessing second-line and even third-line drugs was not a problem for patients at Princess Marina's IDCC - Botswana's government has more money to spend on its national treatment programme than most others on the continent and has also received considerable expertise and support from foreign partners, such as the Bill and Melinda Gates Foundation and the Merck pharmaceuticals company, which donates two of the ARV drugs used in the national programme. Part of the key to the IDCC's success has been in monitoring the viral load, which measures the amount of virus in the system and is the only reliable indication that a patient is harbouring resistant mutations of the virus. A drug-resistant patient can look and feel healthy, and even have a normal CD4 count, which measures the strength of the immune system, Avalos explained. A national protocol to manage first-line drug failure is being rolled out in Botswana and will include training in how to track viral loads, but Avalos predicted that monitoring drug resistance would be "our biggest challenge" in African countries that cannot afford to do frequent viral load tests. A new multi-country study funded by GlaxoSmithKline, the British Department for International Development (DFID) and Antiretroviral Therapy in Lower Income Countries (ART-LINC), aims at a better understanding of the factors that affect adherence in poor countries. Based on a small pilot study at Princess Marina last year, researcher Sara Nam of the London School of Hygiene & Tropical Medicine found the biggest factors were not socioeconomic, but psychological and emotional issues similar to those of patients in developed countries: the degree to which patients accepted their HIV status, the amount of support they received from people close to them, and the level of faith in their doctors and the drugs. The multi-country research, now recruiting participants, will include questions about patients' religious beliefs, use of traditional medicines, how concerned they are about stigma, whether they are breadwinners and their alcohol use. Poor adherence is the biggest but not the only cause of drug resistance. Some of the patients Avalos treats, particularly women who have difficulty negotiating condom use, contract resistant strains of the virus by having unprotected sex with HIV-positive partners. Drug resistance is rising in countries where ARVs are not widely available in government programmes and people buy the medicines from the private sector and then interrupt treatment during periods when they cannot afford them. Patients often switch to free drugs when they become available without informing their doctors of which ARVs they were taking previously. According to Bussmann, prescribing a single dose of the ARV drug, nevirapine, to pregnant women - the most common method of preventing mother-to-child-transmission in Africa - can also cause resistance problems when they begin ARV treatment, but "It's too early to say what will happen in the longer term," he said. Previous assumptions about high numbers of patients defaulting on their medication have proved false in Botswana, but no one knows if other countries with less infrastructure and fewer resources will have similarly good outcomes or access to second-line drugs. Perriens of the WHO believes such concerns may be premature, considering that only 20 percent of people in need of treatment in developing countries are currently receiving it: "Our worry about the possible unavailability of second-line drugs should not absorb the energy we need to ensure people get their first chance of survival, which is first-line treatment."