Improved prognosis

Until early 1996, estimates of the proportion of people with HIV who would develop AIDS and the time this would take to occur varied from 50 to 100% and from 18 months to 25 years. The reasons for the discrepancy were several: some people develop AIDS far more quickly than others and early estimates of the time taken to develop AIDS were based on the earliest AIDS cases: the people likely to have developed AIDS most quickly.

As time went on it became clear that significant proportions of HIV-positive people remain healthy for more than 18 months after infection. Researchers were able to see that this period was actually much longer as cohorts were followed for greater periods of time. The monitoring of large cohorts over many years has also allowed scientists to observe trends in disease progression, and to compare predictions with actual rates of disease progression.

A picture of the natural history of HIV / AIDS was formulated prior to the introduction of antiretroviral therapies based on a number of cohort studies. In the absence of treatment, the average time to symptomatic HIV disease was estimated to be eight years, and average time to death was 13 years. Of course, some people developed AIDS more quickly while others progressed more slowly.

Since 1996, treatments have improved and there have been dramatic changes in the health and life-expectancy of HIV infected persons.

Several studies have been published on risk of progression in the era of highly active antiretroviral therapy (HAART). A large cohort study involving over 12,500 people with over 24,300 person-years of follow-up found the following factors associated with a poor prognosis after starting HIV treatment:

• CD4 cell count less than 200 cells/mm³.

• Viral load above 100,000 copies/ml.

• Age above 50 years.

• Injecting drug use.

• Centers for Disease Control and Prevention stage 3 AIDS diagnosis (Egger 2002).

More recent studies have also suggested that patients with higher immune system activation prior to infection with HIV experience a more rapid progression of HIV disease. This immune activation may be due to a higher number of previous infections or a genetic predisposition to immune activation (van Asten 2004).

There is a high risk of death in patients who have experienced treatment failure to all the three main classes of anti-HIV drugs. According to the PLATO study, which involved almost 2490 patients, 15% of people who had failed the three main anti-HIV drug classes die within three years. The risk is highest for patients who stop taking anti-HIV drugs or have CD4 cell counts below 50 cells/mm³. Other factors which significantly increased the risk of death included a prior AIDS-defining illness, age and injecting drug use (Lundgren 2003).

For further discussion of the way antiretroviral treatments have impacted on the health and life expectancy of people with HIV, see Anti-HIV therapy: Effectiveness of HIV therapy.

Recent infection and speed of progression

Several studies have reported contradictory findings regarding a possible acceleration of HIV disease progression among people infected more recently. There is some evidence that people infected in Italy during the 1990s had a more rapid rate of disease progression than those infected in the 1980s. Italian researchers speculate that the virus may be mutating and becoming more aggressive (Sinicco 1997). However, British scientists say that there is no evidence of an increase in the rate of disease progression in the United Kingdom.

The Swiss HIV Cohort Study has provided some support for the Italian results, reporting that more rapid CD4 cell count decline was associated with female sex, injecting drug use and year of seroconversion. The effect of year of infection was only observed through an interaction with the other factors (sex and injecting drug use) which were not explored in the Italian study (Vanhems 1999).

The Italian researchers suggest that their findings may be more reliable because they studied a diverse group of people with HIV including those infected through heterosexual sex, homosexual sex and injecting drug use, while other studies have focused mainly on gay men. However, the most likely explanation for this discrepancy is that the result reflected the way the study was conducted, rather than any real change is the course of HIV infection.

Among the most recently infected people, those who are experiencing the least disease progression may be under-represented in the study, because their good health means that they are less likely to have attended the clinic. Similarly, people who are experiencing faster than average disease progression are more likely to have attended clinic and been included in the study, giving the misleading impression that their faster rate of progression is typical of others infected around the same time.

A team of scientists in Antwerp recently published data which also contradicts the Italian study. Rather than looking at CD4 cell counts, this study looked at viral fitness, that is the rate at which peoples HIV viruses could replicate in a test tube (Arien 2005). The scientists studied twelve virus samples taken between 1986 and 1989 and twelve more taken between 2002 and 2003. The viruses obtained from the more recent samples did not replicate as well as the viruses from the 1980s, suggesting that HIV is gradually evolving to become less fit.

This may be because less fit viruses cause disease to progress more slowly and so have a longer chance to be passed on, gradually becoming more predominant in the population. However the Dutch study was not able to distinguish how much of this effect may have been due to changes in the virus caused by the pressures of drug therapy.

Drug-resistant virus and disease progression

The acquisition of drug-resistant virus has been correlated with more rapid disease progression. For example, in some studies AZT (zidovudine, Retrovir)-treated people who developed the codon 215 mutation (indicating high-level AZT resistance) had a more rapid rate of disease progression compared with those who did not develop this mutation.

At first it was thought that the drug-resistant strain of HIV might be more aggressive. However, the most likely explanation is that the development of AZT resistance occurs more frequently and more rapidly among people with high viral load, which is known to be a predictor of a poor prognosis.

Current guidelines recommend that patients continue to take antiretroviral therapy after the development of resistance when no alternative drug regimen is available, in order to suppress HIV as low as possible and prevent the re-emergence of wild-type virus. This approach has been supported by an observational study in 572 patients, which failed to show an association between the number of resistance mutations in incidence of opportunistic infections or death with a median follow-up of 15 months (Lucas 2004).

In people who are infected with drug-resistant HIV, there is evidence that the rate of CD4 cell count decline is similar to that in people with wild type virus in the absence of drug therapy. In a study of 124 patients, 17% of whom had been infected with HIV resistant to at least one drug, there was a non-significant trend towards more rapid CD4 cell count decline in the first year after seroconversion, but no difference thereafter, when both groups showed a mean loss of 56 cells/mm³ per year (Bhaskaran 2004).

See Transmission of resistant HIV in Anti-HIV therapy: Resistance and Viral fitness, drug resistance and the immune system in Anti-HIV therapy: Restoring the immune system for further discussion of resistance and the immune system.

CD4 and CD8 T-cells and viral load

It is well established that the higher a person's viral load, the greater the risk of disease progression or death. However, the effect of CD4 cell counts is less clear. While low CD4 cell counts are associated with a greater risk of opportunistic infections, there have also been some observations that disease progression is more rapid in patients who have low CD4 cell counts soon after infection (Goujard 2006). However, this study found that viral loads in primary infection were not linked to rates of disease progression, possibly due to their variability at this stage of infection. In contrast, patients with higher levels of HIV DNA incorporated into their blood cells' genetic material were also more likely to progress to a low CD4 cell count.

In contrast, a recent study of African sex workers has found that higher viral loads during primary infection are linked to an increased risk of death, as are the number of symptoms of primary HIV infection (Lavreys 2006).

In patients with more advanced disease, there is evidence that viral load is less important in predicting disease progression among people who have low CD4 cell counts. One study of 37 men with advanced HIV disease found that immune activation, measured by high levels of the CD38 antigen on the surface of CD4 and CD8 T-cells, is associated with shorter survival. In contrast, high levels of CD8 T-cells displaying a different activation marker were associated with longer survival. There was no difference in viral load or naive immune cell numbers between the short and long-term survivors. These findings suggest that in advanced HIV disease, T-cell activation is the key determinant of survival time (Giorgi 1999).

Another study backing up the association between immune activation and disease progression found that in people not receiving anti-HIV treatment, a low dose of the immunosuppressive drug prednisolone which suppresses T-cell activation, slightly increased CD4 cell counts over three years. Patients not receiving prednisolone in this study experienced a substantial drop in CD4 cell counts over the same time period (Ulmer 2005).

The nature of the HIV-specific CD8 T-cell response may also be crucial in determining the rate of disease progression, although this requires more investigation. One study found that a high level of cytotoxic T-cell precursors and a strong p24 T-cell response were associated with long-term non-progression (Greenough 1999). A different study in Zurich also found that HIV-specific T-cell responses slow disease progression. A slower rate of the fall in CD4 cell counts was associated with stronger HIV-specific CD4 and CD8 T-cell responses (Oxenius 2004).

Researchers in Paris compared a number of immune function markers in long-term non-progressors. While they found that HIV p24-specific CD4 and CD8 T-cell responses were negatively correlated with the amount of HIV integrated into T-cells, the two immune factors that predicted if a person would still be a long-term non-progressor after nine years of infection were the presence of HIV p24-specific CD4 T-cell responses and presence in the blood of HIV-gp41 antibodies belonging to IgG2 subtype (Martinez 2005).

See Immune responses to HIV in The immune system and HIV: How HIV damages the immune system for further discussion of the role of T-cell responses to HIV.

Viral phenotype

HIV is often broadly classified as syncytium-inducing (SI) or non-syncytium-inducing (NSI). SI strains cause cells to clump together and have been associated with more rapid disease progression than NSI strains.

A six-year study of 132 people found that those who originally had undetectable viral load had a 95% survival rate. Those who had NSI virus had a 78% survival rate and people who had SI virus had a 21% survival rate at six years. Furthermore, the development of the SI-phenotype was associated with CD4 cell count decline, rather than viral load increase. The investigators concluded that phenotype testing for SI or NSI virus could offer an additional predictive marker for progression of HIV infection (Kupfer 1998). However other studies have not distinguished any independent effect of SI upon disease progression (Giorgi 1999; Koot 1999).

See Strains of HIV in The immune system and HIV: How HIV damages the immune system for more information.

Viral sub-type

Different sub-types of HIV-1 have been shown to be associated with differing rates of disease progression. For example, researchers in Senegal observed AIDS incidence rates of 3.5 per 100 person-years in women infected with sub-type A, 16.0 for sub-type D and 14.5 for sub-type C. A similar study of almost 1050 individuals in Uganda found that individuals infected with sub-type D were 29% more likely to die of AIDS or experience CD4 cell count declines during any six month follow-up period (Kaleebu 2002).

However, a Swedish study has found that HIV sub-type is not a major factor on disease progression. Researchers compared disease progression among 49 ethnic Swedes and 49 ethnic Africans and found that viral sub-type did not affect progression. Further, they looked at 126 people infected with various sub-types, and found that sub-type did not affect CD4 cell count decline, viral load or clinical disease progression (Lidman 1999).

The virulence of a particular HIV strain may also affect the rate of progression. A 1994 study examined 25 people who were infected with HIV from transfusions and whose eight corresponding blood donors could be identified. The study found that progression to AIDS and death was significantly slower among people who received blood from donors who themselves had not subsequently progressed to AIDS, compared with those who received blood from donors with faster disease progression. This implies that the donors with more rapid disease progression had more virulent HIV strains that were transmitted to the recipients. More virulent HIV strains may replicate more quickly or which preferentially infect CD4 T-cells. HIV strains that are resistant to anti-HIV therapy have also been associated with a poor prognosis.

However, other studies have shown that different people infected with an identical HIV strain may have different rates of disease progression. In 1993, researchers identified a cluster of 13 inmates who were infected with the same HIV strain. During the following two years, two developed AIDS and another two developed CD4 cell counts below 200 cells/mm³, while others have much slower progression. This research indicates that the individual's immune response to HIV may play an important role in their rate of progression (McMenamin 1995).

Viral variations

There is evidence that genetic diversity of HIV is another factor influencing disease progression. Mutations in the HIV nef gene have been associated with non-progression, according to data from the Sydney Blood Bank Cohort. This group of individuals were all infected with HIV that contained a crucial deletion on the nef gene. To date, none of these individuals has developed AIDS, but recent reports have suggested that some are slowly experiencing damage to their immune systems.

Other variations or mutations in the genetic make-up of HIV may also affect the speed of disease progression. For instance, American researchers have linked long-term non-progression and slow progression to V2 region extensions in env (Wang 2000). More recently, researchers from the Mayo Clinic in Rochester, Minnesota have linked mutation R77Q in the HIV protein Vpr to delayed disease progression (Lum 2003).

Dual infection and superinfection

It is possible to be infected with more than one version of HIV from the same or different subgroups. This is known as dual infection or superinfection. Documented instances of superinfection have been associated with disease progression and the failure of antiretroviral therapy. See the discussion of 'Superinfection' in Transmission of resistant HIV in Anti-HIV therapy: Resistance.

Reports of increasing unsafe sexual practices among HIV-infected people in some western countries suggest that dual and superinfection may become more prevalent. As a result, new evidence that dual infection causes faster HIV disease progression is of concern. However, it is becoming more certain that patients who have been infected with HIV for more than two to three years may have a greater degree of immune protection against superinfection with a second strain of HIV. This needs confirmation in future studies.

Researchers from the University of Washington and the Johns Hopkins University School of Medicine in the United States and the universities of Natal and Cape Town in South Africa identified five dually infected patients among their cohorts of individuals with known seroconversion dates for HIV. Four had dual infections with two variants of HIV subtype B and one had dual infection with two variants of HIV subtype C. In four cases, two variants of HIV were present when HIV infection was first identified, and one person became superinfected with another HIV variant a year after seroconversion.

Disease course in these five dually infected people was compared with disease progression in 34 monoinfected seroconverters drawn from existing cohorts. Dually infected individuals had a three-fold higher risk of disease progression during the follow-up period. The average time from seroconversion to development of an AIDS-defining illness or death was less than 3.4 years, and the average time from seroconversion to a CD4 cell count below 200 cells/mm³ was 3.1 years. In comparison, the monoinfected seroconverters took between eight and ten years to develop AIDS (Gottlieb 2004). Cohort data suggest that only 2 to 3% of people are likely to develop AIDS within two years of seroconversion.

Nutrition and micronutrient supplements

Several studies have found that low levels of vitamins A, E and B₁₂, as well as the mineral selenium in the blood were associated with faster disease progression (Fawzi 2005). In the United States an observational found that daily use of a multivitamin tablet was associated with a 30% reduction in the risk of progression to AIDS and with higher CD4 cell counts.

In another study higher intakes of niacin, vitamins B₁, B₂, B₆ and C were associated with slower disease progression and a 40 to 60% reduction in the likelihood of death after eight years. However vitamin A was found to be associated with increased progression if levels of intake exceeded 20,000 international units per day. Vitamin A was also associated with increased risk of transmission of HIV to an unborn child in pregnant women. In developing countries children born to women taking multivitamins was separately associated with decreased risk of death, increased attainment of weight by 24 months and increased CD4 cell counts.

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