Antiretroviral therapy in HIV

The advent of antiretroviral therapy has dramatically improved the prognosis of HIV-infected individuals, but too many patients present late for care. European initiatives to implement HIV testing in the primary care setting are essential

Manuel Battegay* MD Chief Luigia Elzi Division of Infectious Diseases & Hospital Epidemiology University Hospital Basel
Basel Switzerland *Board Member Swiss HIV Cohort Study/
Vice President European AIDS Clinical Society

Potent antiretroviral therapy (ART) has dramatically improved the prognosis of HIV-infected individuals close to a normal life expectancy in a significant proportion of treated individuals. On starting ART, immune deficiency can be prevented or, if already present, reconstituted.[1,2] Nevertheless, 10–30% of patients in western countries, including Europe, present late for care, when CD4 T-cells have already fallen below 200 cells/ìl and symptomatic HIV disease has occurred.

The therapeutic response and prognosis are strongly dependent on strict adherence with treatment. Drug side-effects, toxicities, drug– drug interactions and HIV drug resistance are still obstacles that in one way or other may limit therapeutic success.

For hospitalised patients with late disease and possibly AIDS-defining complications, intensive care has significantly altered the prognosis in the short as well as in the long term.

Importantly, as HIV-infected patients become older, long-term toxicity of antiretroviral drugs may play an important role in increasing the risk of cardiovascular diseases.

At the population level, the impact of ART on mortality will depend on preventing late diagnosis of HIV and HIV itself among other factors. Hence, European initiatives to implement HIV testing in the primary care setting are essential to detect HIV-infected individuals in time.[3,4]

Epidemiology of HIV
HIV/AIDS remains a major public health issue in Europe, where an estimated 2.4 million individuals are currently living with HIV/AIDS, many of them in Eastern Europe.[5] It is paramount to implement preventive measures to decrease HIV incidence. In this context, expanded access to ART and treatment itself may reduce HIV transmission as optimally treated individuals are much less likely to transmit HIV.[6] So far, it has been possible to almost completely prevent HIV transmission from pregnant women to their newborns through ART, and to significantly reduce the risk of sexual transmission between discordant couples.

At the population level, expanded access to ART has been associated with a substantial reduction in HIV incidence.[7] For instance, a mathematical model demonstrated a potential reduction in HIV incidence of 37%, 54% and 62% if the ART coverage would be increased from 50% to 75%, 90% and 100%, respectively, assuming a stable adherence to treatment.[7]

At a political level, the G8 summits in 2005 and 2007 in Gleneagles, Scotland, and Heiligendamm, Germany, were aware of the increasing need for millions of HIV-infected  individuals to receive treatment. HIV/AIDS, tuberculosis and malaria were defined as the three currently most devastating diseases affecting the developing world. Together, these three infectious diseases claim more than 6 millions lives annually. The support for universal access to treatment was strongly reinforced by the recent 2008 G8 summit in Hokkaido Toyako, Japan.

[[HHE.P30]]

For the networking and coordination of European national programmes with partners in the South, the European and Developing Countries Clinical Trials Partnership (EDCTP) was founded in 2003. It aims to develop and test new clinical tools against HIV/AIDS, tuberculosis and malaria. At the forefront of these initiatives, European countries such as Germany, Italy, France, the United Kingdom, Russia and the United States provide the financial resources, in particular contributing to the Global Fund, a unique global public–private partnership aiming at fighting the above mentioned diseases, HIV/AIDS, tuberculosis and malaria.

With the introduction of ART and the advent of protease inhibitors in 1994–1996 the hope of curing HIV was an over-optimistic vision. Hence, the therapeutic strategy aimed to treat as many individuals as possible – in other words, “hit hard, hit early”.

Although HIV viraemia could durably be reduced to levels that are below the limit of detection, the virus was shown to persist in lymph nodes and other reservoirs, soon demonstrating that HIV cannot be eradicated with currently available antiretroviral drugs and that lifelong treatment is required. Therefore, the key goal of ART is to achieve sustained virological suppression to restore and preserve immunological function, to prevent opportunistic diseases that occur only with a damaged immune system and to reduce mortality.

The long-term virological and immunological efficacy of ART has been documented in many longitudinal studies.[1,2,8–15] Due to the high frequency of long-term toxicity, particularly with first-generation antiretrovirals, the threshold to start ART was defined at a CD4 T-cell count of 200 cells/ìl. This is the threshold where the risk for AIDS-defining diseases starts to increase sharply.

Recent large observational studies, however, support the use of ART in all individuals with a CD4 cell count below 350 cells/ìl, since the incidence rate of both AIDS and non-AIDS-defining conditions, including cardiovascular diseases, liver-related events, renal disease and certain malignancies increased progressively as the CD4 cell count decreased from 350 to 200 cells/ìl.[16–18]

Table 1 illustrates the increase in potency and impact of ART on mortality since 1996. Major European cohort studies such as EUROSIDA www.eurosida.org/EuroSIDA/tabid/59/Default. aspx), the Swiss HIV Cohort Study (www.shcs.ch) and the Danish Cohort Study reported a life prolongation between 10 and 35 years over the last decade, mainly depending on adherence with ART and co-morbidities such as intravenous drug use and/or chronic hepatitis C.

Recently, the large international observational study ART-CC reported a life expectancy of another 43 years for individuals starting ART at age 20 years.[19]

Specifics of antiretroviral therapy
Combination antiretroviral therapy should be started before the risk of opportunistic diseases increases – that is, at the threshold of 350 CD4 T-cells/ìl. Time should be taken to prepare a patient in order to optimise their adherence and
understanding of HIV infection.

According to European guidelines, a triple combination therapy of two nucleoside reverse transcriptase inhibitors with either a nonnucleoside reverse transcriptase inhibitor or a boosted protease inhibitor is the preferred initial regimen.[20]

Several antiretroviral drugs are currently available with somewhat different efficacy, pill burden and potential side-effects. The presence of transmitted HIV drug resistance, co-morbidities, interactions with other required medications, psychiatric disorders including active drug use, and socioeconomic barriers should be carefully considered before starting ART.

With these therapies virological and immunological outcome is excellent. For example, a recent study of the Swiss HIV Cohort Study demonstrated that the overall first-year response was between 87.1% and 96.9% depending on whether treatment had to be changed or not.21 The same study indicated that treatment switch is still very frequent, decreasing only to a minor degree from 2000 until the end of 2005. Because antiretroviral regimens have become much better tolerated, treatment may be changed earlier even if minor side-effects occur.

Conclusion
Prognosis depends much upon the expertise and knowledge of HIV experts, internists and, if needed, intensive care specialists. In view of the public health implications of early HIV diagnosis for reducing HIV transmission and preventing late presentation, HIV testing should be more frequently recommended in all healthcare settings.

That was also the focus of HIV in Europe 2007 – working together for optimal testing and earlier care – an initiative that targeted all states from Europe, in particular those in Eastern Europe such as Belarus, Moldova, Norway, Russia and Ukraine. The mission is to highlight the rising number of people in Europe newly infected with HIV who are unaware of their sero status and to identify political, structural, clinical and social barriers to achieving optimal testing and counselling, and earlier care for HIV/AIDS (www.hiveurope2007.eu).

HIV screening is currently widely recommended for people at risk of HIV infection, but also more and more as a routine test, for example for pregnant women. It is to be hoped that in the future the clinical entity of late presentation will become significantly rarer, HIV infection can be prevented to a much larger degree and universal access to ART for individuals in medical need will become a reality.

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