A cornerstone of efforts to reach universal access targets is sustained dedication to basic research and to the understanding of AIDS pathogenesis, in order for new drugs, novel therapeutic strategies and vaccines to be designed and developed.
The availability of potent combinations of antiretroviral drugs in the developed world has resulted in a steep decline in HIV-associated morbidity and mortality. Death rates from AIDS fell by 80% over the four years following the launch of highly active anti-retroviral therapies in Europe and North America. Following their more widespread introduction in the second half of the 1990s, it also became clear that issues relating to adherence, toxicities, immunological and virological failure of treatment, and occurrence of resistance all needed to be tackled.
Sustaining long-term adherence
Effective treatment with antiretroviral drugs requires long-term adherence. From an operational research point of view, monitoring the uptake of treatment involves: defining optimal measures of adherence which can be used in resource-poor countries; assessing the validity of self-reports, compared with other methods such as pharmacy records or electronic monitoring systems; and identifying ways to encourage more accurate reporting by patients.
Evidence shows that the variables with the strongest effect on adherence are treatment-related. These include the complexity of the regimen, side-effects, the "battle fatigue" that results from long-term use, and patients' attempts to remedy these problems by modifying the dosage or administration of drugs. Misperceptions and lack of trust regarding the medication's effectiveness further compound these problems. Women face unique obstacles related to child care, lack of partner support, and the attitudes of peers and family members. Among the social variables that are found to affect adherence, stigma and fear of disclosure have the strongest effects (17). In addition, costs matter: copayment is detrimental to long-term adherence (18).
Questions about long-term use remain, despite new ideas regarding barriers to adherence. The increased availability and lower costs of drugs, and the advent of fixed-dose combinations, have raised hopes of reducing access problems by lowering cost. Initiation and continued use are influenced by different factors, however, so attention has to be focused on use over the long term. Recent studies show that patients in Haiti and a number of African countries take about 90% or more of their drugs (19, 20). This gives cause for optimism. At the same time, however, lifelong use of drugs raises the question of sustainability, for which operational research may provide some insights (21).
A number of interventions (most of them tested in developed countries) have been conducted with antiretrovirals. Individualized education and advice have proved to be successful, especially when associated with participation in support groups. Scaling up treatment will mean sharing responsibilities with health workers who lack formal medical training - allowing health workers to monitor and follow up patients - and this will have profound implications. The extent to which the lessons from successful programmes can be rapidly implemented in diverse settings indicates a rich agenda for operational research, and the key role of innovative knowledge-sharing mechanisms.
Coping with toxicities
The importance of treatment-associated adverse effects in current HIV therapy is illustrated by several studies demonstrating that 40% or more of patients initiating highly active antiretroviral therapies will experience one or more forms of drug toxicity, and consequently may need to modify their regimen within the first year of treatment (22). Examples include hepatic toxicity, rash, diarrhoea, anaemia and peripheral neuropathy. Other adverse effects may become noticeable clinically only after more prolonged exposure to therapy (one to two years) (23, 24).
Innovative ways of assessing the potential toxicity of new drugs are needed at all preclinical and clinical phases of drug development. To ensure that millions of people get the best, sustained treatment, it is imperative that issues of resistance and longer-term safety and tolerability of treatment receive sufficient attention as treatment expansion unfolds. However, drug toxicities will always be preferable to inevitable death in the absence of drug treatment, particularly if concerns over toxicities prevent availablity of treatment in resource-poor settings.
Preventing drug resistance
The issue of resistance by HIV to antiretroviral drugs is a major concern. Evidence from clinics, apart from clinical treatment trials, suggests that the frequency of incomplete virological suppression in people treated with combination therapies may exceed 50% (25). Incomplete suppression results in acquired viral resistance to antiretrovirals. Resistance often occurs to more than one or two of the three drugs that are being taken by the patient, because of cross-reactivity between drugs within a given antiretroviral family. While the emergence of a drug-resistant virus may be associated with a slower immunological decline in some people, virological failure of treatment places people at risk of developing resistance to antiretroviral drugs. They are also at risk of losing treatment options after treatment has been modified several times, and of ultimate immunological failure and morbidity.
Methods are needed that ensure the effectiveness of antiretroviral therapies in preventing virological treatment failure, and novel, more potent drugs will have to be designed that are active on both "wild" and resistant strains of viruses. Since current therapy is capable of suppressing viral replication but not capable of viral eradication from the host, no current therapeutic regimen will be completely successful. Thus, reservoirs of infection are established early and apparently persist in all HIV-infected people irrespective of therapy (26). A systematic and rigorous approach to treatment offers the best opportunity to study and promote adherence and thereby reduce drug resistance and treatment failure (see Chapter 2).
Developing new drugs and strategies
Dozens of new drugs are being researched, including those belonging to the three currently available families of antiretrovirals: nucleosidic and non-nucleosidic reverse transcriptase inhibitors and protease inhibitors. Research and development of new compounds in these three families aims at providing drugs that are more potent, easier to take and better tolerated, as well as new formulations combining several of the drugs in one pill.
The first of a new class of "entry inhibitor" drugs that prevent the virus getting into cells in the first place was launched in 2003. These drugs will probably be the most important new antiretrovirals. They target human cell components, rather than viral components, and therefore the virus should find it more difficult to develop resistance to them. The next class of drugs expected is that of inhibitors of the integration of viral DNA into the host's genome.
The issues of toxicities and insufficient virological and immunological potency are not being solved by current treatment strategies. Therefore, new strategies need to be targeted at immune-based approaches to the treatment of HIV-1 infection, such as therapeutic vaccination, passive immunization or eradication of the "reservoirs" of infection. These approaches represent a vital area of basic and clinical research for the coming years.
Tackling tuberculosis and HIV/AIDS together
Tuberculosis (TB) impacts heavily on HIV morbidity and mortality, as HIV is the most potent risk factor for reactivation of latent tuberculosis infection to active disease. A person dually infected with HIV and Mycobacterium tuberculosis has an annual risk of developing TB ranging from 5% to 15%, compared with the lifetime risk of 10% for someone with an intact immune system.
One component of the strategy to decrease TB-related morbidity in people living with HIV/AIDS is to prevent the progression of latent TB infection to active disease, by offering isoniazide preventive therapy as part of the clinical package of HIV care. This treatment has been shown to reduce the risk of TB in tuberculin test positive HIV-infected individuals by 67% (27). Because of reinfection, however, the effect is relatively brief in communities where TB is endemic. The BCG vaccine for TB does not protect against primary infection and, on average, has a protective effect against active disease of only 50%. A crucial means of improving HIV-related morbidity will be the development of an improved TB vaccine. The many steps needed to identify TB infection, and the need to take treatment for at least six months with periodic evaluations for adverse reactions, mean that the proportion of individuals who complete treatment, even under the best conditions, is small.
In order for isoniazide preventive therapy to be an effective public health measure, further research is needed to understand how to diminish the loss of treatment candidates at each step of the process, and how to find effective, shorter-term treatment with few side-effects. New medication delivery methods (for example, medication skin patches and other depo-preparations) are also required, as are new methods other than tuberculin skin tests to determine cases of infection.