For HIV-infected people who have never been on treatment, viral load is a very good predictor of their chance of developing AIDS in the future. In the normal course of HIV infection, a viral load increase is followed by a CD4 cell count decrease and subsequent illness. Consequently, tracing changes in viral load provides the clearest idea of how quickly the infection is progressing in both men and women.

The discovery that viral load could predict disease progression was one of the most important breakthroughs of 1996. This advance was made possible by a number of large studies into viral load, including research conducted by Dr John Mellors (also see O'Brien 1996; Phillips 1996). Prior to this discovery, the only tool available for monitoring the likelihood of illness was the CD4 cell count.

However, estimates of the risk of developing AIDS associated with a particular viral load have been based on studies of men. These estimates of risk may not be applicable to women due to gender differences in viral load levels (see Viral load in women below).

Viral load may also be an inaccurate predictor of disease progression in people who have taken or are taking anti-HIV treatments. Generally, viral load and CD4 cell count are assessed together. CD4 cell count is considered a better predictor of outcome in people with CD4 cell counts below 50 cells/mm³, although changes in both markers in response to treatment affects risk of disease progression and death (Justice 1999). The impact of treatment on viral load and health are discussed fully in Monitoring treatment with viral load in Viral load, CD4 cell counts and other tests: Viral load.

The MACS study

Researchers have investigated the relationship between an individual's current viral load and risk of AIDS or death in the future. The United States Multicenter AIDS Cohort Study (MACS) was the largest such study, enrolling over 1600 symptom-free, HIV-positive gay men in 1984 and 1985 (Mellors 1997). Blood samples were taken and frozen when they joined the trial and at six monthly intervals thereafter. Ten years later, the doctors went back to the samples and tested the viral load, then compared each individual's test results with his medical history.

The study confirmed that an individual's viral load may provide a very accurate indicator of the risk of disease progression. The researchers found that men with viral load above 55,000 copies/ml on the Roche RT-PCR test or 30,000 copies/ml on the Chiron bDNA test had a very substantial risk of developing symptomatic illness within three years. For example, if a man had a viral load above 55,000 copies/ml and a CD4 cell count above 750 cells/mm³, he had a 33% risk of disease progression within three years. If his viral load was above 55,000 copies/ml and CD4 count was below 200 cells/mm³, he had an 86% risk of developing AIDS within three years.

Conversely, men with viral loads below 7000 copies/ml on the Roche RT-PCR or 3000 copies/ml on the Chiron bDNA had a very low risk of developing symptomatic illness: less than 4% in any CD4 category. It was impossible to evaluate the risk for people with low CD4 cell counts and low viral load because there were too few of them.

The MACS study found that measuring viral load can identify different risks of disease progression between two symptom-free people who had the same CD4 cell count but different viral load. CD4 cell counts on their own are much less reliable predictors of disease progression, although looking at both an individual's viral load and CD4 cell count gives the most precise prediction. There is a strong link between viral load and the subsequent rate at which the CD4 count declines.

Seroconversion

It has also been shown that viral load during seroconversion may be predictive of progression. The Italian Seroconversion Study found that high early viral load was associated with a faster progression to AIDS or CD4 below 200 cells/mm³. Older age at seroconversion was also associated with faster disease progression. CD4 cell count soon after seroconversion was not independently associated with HIV disease progression (Lyles 1999).

Viral load over time

Predicting disease progression is also informed by the discovery that HIV viral load slowly increases over the course of the infection. The notion that HIV viral load remains fairly static for years has been disproved. One study analysed blood samples taken over a 17-year period. It found viral load increased by an average of 0.12 log₁₀ per year, although a higher rate of increase was predictive of more rapid disease progression (Sabin 1998). Another study found that viral load increased annually by 23% (Lyles 1999).

The rate of viral load increase during the early years of chronic infection is predictive of time to AIDS. A study of 269 seroconverters found that initial viral load results and the slope of viral increase were highly associated with disease progression (Lyles 2000).

Viral load in women

A meta-analysis of studies in which rates of disease progression had been compared by gender found that on average, the viral load of women was 41% higher at any given CD4 cell count than men. Nine studies were available for analysis, and all but one showed lower viral load in women (Napravnik 2002).

Previously, key studies into viral load and disease progression looked mainly at male-only cohorts of gay men and haemophiliacs. It was largely assumed that there was no difference between men and women in terms of viral load and disease progression. However, a growing body of evidence shows that there is a sex-based difference in viral load.

The findings reinforce a considerable body of research into gender and viral load.

One study found that female injecting drug users (IDUs) had significantly lower viral loads than male IDUs, even when CD4 cell counts were matched. A review of viral load measurements using three different techniques found that viral levels in women were between 38 and 65% lower than those found in male IDUs at similar CD4 cell counts. Women also developed AIDS-defining illnesses at a similar speed to men in the cohort, despite having lower average viral load at baseline (Farzadegan 1998).

Another study comparing disease progression among male and female IDUs found no difference in CD4 decline nor mortality between men and women, but when controlling for age and CD4 cell count, women progressed to AIDS 1.6 times more quickly than men (Webber 1998). Two previous studies had also found that HIV viral loads were 50% lower in women when controlling for CD4 cell count (Bush 1996; Katzenstein 1996).

Data from an Italian cohort and the United States HIV Epidemiology Research Study (HERS) both found that when men and women are matched for CD4 cell count and stage of disease, women tend to have lower viral loads. The Italian Seroconversion Study also found women have significantly lower viral loads than men but the same rate of increase over time (Moroni 1999).

Data from the MACS cohort of HIV-positive gay men and from the US Women's Interagency HIV Study (WIHS) was assessed and reported in 1999 by a team from New York. Viral load measurements for 1511 untreated men and 1262 untreated women were controlled for CD4 cell count, age, clinical factors and injection drug use. At CD4 cell counts below 200 cells/mm³ there was no difference in viral load levels between men and women. However, at CD4 cell counts between 200 and 500 cells/mm³, women's viral load was 40% lower than men's and at CD4 cell counts above 500 cells/mm³, it was 24% lower. Older age, clinical symptoms and no prior history of injection drug use were associated with higher viral load levels. Though the authors were unable to explain the differences observed, they concluded that at higher CD4 counts, viral load results may need to be adjusted for gender (Anastos 2002).

Two research teams have found no evidence to support the claim of a sex difference in viral load and disease progression from cohorts that included both IDUs and non-IDUs (Egger 1999; Moore 1999). Others have found inconclusive results, with the issue of injecting drug use confounding results. A review of the Swiss HIV Cohort Study found that viral load was slightly lower among female injecting drug users, but not among non-injecting, heterosexual women (Junghans 1999). The Swiss Cohort Study has also found that year of seroconversion, female sex and injecting drug use are associated with a faster decline in CD4 cells (Vanhems 1999). Another study found that the gender difference in viral load was greater among non-IDUs than among IDUs (Moroni 1999).

The reason for the sex difference in the relationship between viral load and disease progression risk is unknown. A number of theories have been put forward, such as superior immune response to viral infections in women due to hormonal factors, reduced viral production in women, or exposure to low amounts of HIV due to mode of transmission.

Implications for treatment strategies

Some researchers have expressed doubt about whether current estimates of progression risk based on viral load levels are relevant to women. Furthermore, viral load differences may affect on womens ability to access antiretroviral therapy and clinical trials.

Based on the above findings, it has been suggested in the United States that current viral load thresholds for starting treatment may not be appropriate for women, and that it might be prudent to revise the threshold for starting therapy down to 5000 copies/ml for women. However, the guidelines on antiretroviral therapy published by the International AIDS Society in January 2000 rejected this idea.

On the basis of the MACS data, the IAS panel argued that sex differences in viral load disappear as immune deficiency advances. Subsequent revisions of guidelines in the United States and the United Kingdom have not proposed gender-specific thresholds for starting treatment, perhaps because the effect of a 40% difference in viral load at levels below 100,000 copies/ml is likely to be marginal. Viral load would have to rise above 70,000 copies/ml to equate with a level of 100,000 copies/ml seen in the predominantly male cohort studies that have been used to define the threshold beyond which treatment response is reduced. At this level of viral load, a clinician is already likely to be proposing more regular monitoring and careful consideration of treatment if the CD4 cell count is below 350 cells/mm³. Furthermore, there is no evidence that women who start treatment with viral load above 50,000 copies but below 100,000 copies/ml have a worse response to treatment.

Ethnicity, viral load and prognosis

Research carried out at St Thomas's Hospital in London suggests that ethnic origin may affect the interpretation of viral load results. An analysis of 322 patients was carried out using the Multiplex bDNA assay, which has been shown to have greater sensitivity to the non-B HIV subtypes typically found among Africans with HIV. Thirty five per cent of the group were Black Africans, and multivariate analysis showed that at any given CD4 cell count, Black African patients had significantly lower viral load (Saul 2001).

Viral load not the only predictive factor

Viral load intersects with other factors in determining disease outcome. Factors such as age and gender (as discussed above) have been shown to affect disease progression. For example, a study among 165 people with haemophilia found that measuring viral load between one and three years after seroconversion could help to identify people who are likely to become long-term non-progressors. However, the study also found that older people were at greater risk of disease progression than younger people who had the same viral load (O'Brien 1996). Another study found that HIV-infected people over 50 years of age on average have lower CD4 cell counts, higher viral loads and greater risk of disease progression than younger people. The reasons for this are not understood, although the presence of other diseases in older people may be a factor.

Another study suggested that viral load may not be a useful predictor of disease progression for people with CD4 cell counts below 50 cells/mm³, because the immune system is so severely damaged that viral load is not of prime importance (Yerly 1996).

Implications of predicting prognosis

By measuring their viral load, untreated individuals can get a good impression of their risk of disease progression. This may help some decide whether to start anti-HIV treatment, and if so, how aggressive a treatment regimen might be needed. However, it remains unclear to what extent it is possible to alter the poor prognosis of a high viral load by using anti-HIV drugs to lower viral load.

Prognosis in treated people seems to be affected by several factors including baseline viral load and CD4 cell count, reduction in viral load and increase in CD4 cell count following treatment, and prior illnesses. One study found that high baseline viral load and failure to achieve a substantial reduction in viral load were associated with a greater risk of opportunistic infection, regardless of CD4 cell count (Swindells 2002). This suggests that viral load response alone may give an important indication of prognosis, although CD4 count remains significant.

In addition, a recent study demonstrated that the viral load at four weeks after starting antiretroviral therapy was strongly predictive of long-term virologic control: a reduction to below 1000 copies/ml at this stage showed an 83 to 95% probability of a viral load below 50 copies/ml at 24 weeks, regardless of baseline viral load (Smith 2004).

Viral load in children

See Differences between adults and children in Anti-HIV therapy: Options for children for further discussion of the prognostic value of viral load measurements in children.

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