The effectiveness of highly active antiretroviral therapy (HAART) is clearly demonstrated by the fall in opportunistic infections since 1996 in countries where HAART is widely available.

Hospitalisation in decline

In the United Kingdom, hospital admissions among people with HIV began falling prior to the introduction of HAART. However, admission fell dramatically during 1996 and 1997 following the widespread uptake of HAART by people with HIV in the UK. Of almost 1810 patients at the Royal Free Hospital in London followed for nearly two years, the time spent in hospital fell from 5% in 1988 to 1% in 1997 (Mocroft 1999).

Ten leading HIV clinics in England reported that the uptake of antiretroviral therapy among people with AIDS coincided with decreased use of inpatient hospital services. In 1996, each AIDS patient spent an average of 20 days in hospital. In 1997, this figure fell to 11 days (Beck 1999).

However, American figures indicate that uneven access to HIV-specialist healthcare and uptake of antiretroviral therapy have produced uneven impact on hospital admissions. For example, HIV-related admissions at a private hospital in Chicago fell by half between 1995 and 1998 in contrast to a very minor fall in admissions to the largest public hospital (Kumar 2000).

The reasons for hospital admission have also changed in the era of HAART. One study found that the reasons for hospital admission among those on HAART included renal failure (25%), liver failure (20%), cardiovascular disease (11%) and cancer (7%; Gilmore 2000).

Most recently, there has been evidence of a rebound in hospital admission rates among people with HIV in the United States. Data on over 4000 AIDS patients in San Diego indicated that admission rates fell from 10 per 100 person months in 1993 to 3 per 100 person months in 1997. However, since that time, admission rates have risen to 8.6 per 100 person months in the last quarter of 1999 (Bauer 2001).

Incidence of OIs in decline

The incidence of opportunistic infections declined with the uptake of antiretroviral therapy and the risk of illness has continued to fall over time in the era of HAART (Mocroft 2003).

During the late nineties, the incidence of most opportunistic illnesses fell. Research undertaken by the Centres for Disease Control in the US found that the incidence of three of previously common opportunistic infections (PCP, MAI and CMV retinitis) fell from 21.9 in 1994 to 3.7 per 100 person years in mid-1997 (Palella 1998). Data from the Swiss Cohort Study has also found a dramatic 85% reduction in the number of opportunistic infections between 1992 and 1997-1998 (Egger 1998).

A large prospective cohort study from Switzerland found further evidence of a dramatic reduction in new opportunistic infections (OIs) among people who commenced antiretroviral therapy. Comparing new OIs in the six months before HAART and the three months after. In terms of incidence per 100 person years, the incidence of oesophageal candidiasis fell from 3.14 to 1.02, CMV from 2.24 to 0.65, KS from 2.02 to 0.14, PCP from 2.35 to 0.22, and toxoplasmosis from 1.45 to 0.18. In total the incidence of OIs per 100 person years fell from 15.1 to 3.57. As time on therapy increased, the number of new OIs further decreased. People with a baseline CD4 count below 50 had a greater risk of a new OI after starting treatment, compared with those who had a baseline CD4 count between 51-200 (Ledergerber 1999b).

However, the incidence of some opportunistic infections has not declined as rapidly as others. The changing profile of opportunistic illnesses in the era of HAART is discussed below.

There has been some debate about whether the incidence of opportunistic illnesses has continued to decline since the early years of HAART. For example, American researchers have reported that a `substantial' number of cases of PCP continue to occur in patients who have been prescribed PCP prophylaxis, suggesting that resistance to sulfonamide drugs may have become more frequent in the community. However, recent data from the EuroSIDA team indicates the risk of AIDS has fallen since the early days of HAART (Mocroft 2003).

Changing nature of opportunistic infections

Opportunistic infections continue to occur among people with untreated HIV infection, or in people who have found treatment intolerable or ineffective.

However, a new form of opportunistic infection has been documented in people who have responded to treatment - immune recovery illness. Symptoms of CMV retinitis or hepatitis B may occur as the recovering immune system regains the ability to attack these infections. Other conditions that may re-emerge following the commencement of HAART are herpes zoster, herpes simplex, MAI and TB. Research suggests that such immune recovery illnesses are transient, although severe illness may pose problems for the continuation of anti-HIV treatment.

Immune restoration following antiretroviral therapy may assist in the treatment of other symptoms such as diarrhoea and KS lesions. It may also make secondary prophylaxis for illnesses such as PCP and CMV unnecessary if sustained CD4 cell count increases occur, although stopping secondary prophylaxis remains a serious decision. For further discussion of immune-reconstitution illnesses and ceasing prophylaxis, see the entry Prophylaxis and immune recovery in the section Restoring the immune system.

In the age of HAART, there is some evidence that opportunistic infections may occur at higher CD4 cell counts than previously established. Australian research of all new AIDS-defining illnesses between 1992 and 1997 found that opportunistic illnesses developed at higher CD4 cell counts in 1997 than 1992 to 1995. This suggests that immune systems may be weakened despite a maintenance or recovery of CD4 cell counts. Contrary to earlier reports, non-AIDS-defining illnesses do not appear to be higher among people with mild immune impairment (Grulich 2002).

Further data from the EuroSIDA cohort has confirmed that the spectrum of HIV-related diseases has changed. Whilst opportunistic infections such as CMV retinitis and MAI, which occur at very low CD4 counts, have become less common. The extent to which HAART has reduced the incidence of particular opportunistic illnesses has been somewhat uneven.

In the contemporary setting, AIDS-related illness and death among people with access to antiretroviral therapy is likely to be due to cancer, liver disease, renal disease, non-Hodgkin's lymphoma and bacterial infections (Ahmad 2001; Ashby 2003; Boumis 2001; Grulich 2001; Mocroft 2002). AIDS dementia as a proportion of AIDS-defining events also increased during the 1990s.

Of course, standard opportunistic illnesses still occur among people who do not get diagnosed with HIV until they have advanced disease. In England and Wales between 1997 and 2002, 2660 people were diagnosed with HIV when they already had severe immune impairment (Chadborn 2003).

Survival associated with OIs

According to one American study, people diagnosed with illnesses such as PCP, CMV, candidiasis, and MAI are living longer. However, survival time of people with toxoplasmosis, AIDS dementia, and visceral KS was unchanged, and survival of people with bacterial pneumonia worsened after 1995 (El Sadr 1999).

Neurological conditions may not be as responsive to HAART as other infections - possibly due to low drug levels in the brain and the central nervous system - but there is increasing evidence that survival is extended by HAART treatment in people with neurological conditions such as PML, dementia and lymphoma.

For example, a German study found that 71% of people diagnosed with non-Hodgkin's lymphoma who received HAART and cancer treatment had complete remission, compared with 48% of people who received only cancer therapy. Furthermore, the average time of survival from diagnosis to death was only nine months in the total cohort but 83% of those who achieved both a complete remission and responded to HAART were still alive after 39 months (Hoffman 2003). Other studies had found conflicting evidence about whether HAART improves survival in people with NHL (Ledergerber; Thiessard) but this latest study confirms the benefit in people who are well enough to tolerate HAART and chemotherapy.

Recent evidence also shows that people diagnosed with PML are living longer in the era of HAART. For example, a review of the Italian Register Investigative Neuro AIDS (IRINA) Study found that people with PML survived an average of 245 days when prescribed HAART and 66 days when HAART was not available (Antinori 2001).

For detailed discussion of particular opportunistic infections and HAART, and references, see the specific disease entry in Symptoms and illnesses: A to Z of illnesses.

References

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