Until recently, the issue of when to start treatment for HIV has been dominated by the theory of early intervention. The idea of early intervention is to provide prompt medical treatment relatively early in the course of HIV infection, before clinical illness has developed, with the aim of preventing or delaying the appearance of those symptoms. In other words, it is a form of preventive treatment (or prophylaxis) against developing symptomatic HIV disease or AIDS.

There are three possible approaches to early intervention:

• Using anti-HIV drug combinations.

• Using immune stimulants or therapeutic vaccines.

• Using prophylaxes against opportunistic conditions.

In addition, it is worth noting that many people regard maximising their general state of health as an excellent early intervention in its own right, even though it does not exactly fit the strict definition of early intervention. This may range from giving up smoking or other drugs, taking exercise, improving diet, to stress reduction, relaxation and other alternative or complementary therapies. So far, no scientific studies have yet proven that in themselves these things make a difference.

Potential advantages of early treatment

First, studies have shown that there is no truly latent stage of HIV infection. Even though the majority of people with HIV feel perfectly healthy and have no symptoms, HIV is actively reproducing itself in the body from very soon after infection. It has been shown that major sites of viral replication at this stage are in the lymphoid tissue; previous studies may therefore have underestimated the amount of viral reproduction during the asymptomatic phase because they only measured HIV's activity in the bloodstream.

Secondly, it makes sense to try to preserve immune function while it is still intact, rather than waiting until it has already been significantly damaged. An effective early treatment might arrest or at least slow down the loss of CD4 cells, keeping them at a level at which most opportunistic infections do not occur. Some researchers have proposed that treatment in primary infection (around the time of seroconversion) may preserve the immune system's own specific response against HIV, which is lost very soon after the onset of primary infection. See Exposure and primary infection in The immune system and HIV: How HIV damages the immune system for further discussion of this issue.

Thirdly, it is argued that it is better to start treatment at a time when viral load is relatively low (below 50,000 - 100,000 copies) because currently available drug combinations may not have the capacity to reduce viral load to undetectable levels if viral load is higher. If the aim of treatment is to achieve undetectable viral load, in order to avoid the development of resistance and to ensure the long-term durability of a combination therapy regimen, it is likely to be easier to achieve this objective if treatment is started while viral load is not extremely high. One study which supports this theory is a EuroSIDA cohort study. Lower viral load (and higher CD4 count) when treatment was commenced was associated with a more sustained suppression of viral load (Paredes).

However, it is worth noting that the MACS study has shown that the risk of developing AIDS within three years is very low for someone with a viral load under 7,000 copies and a CD4 count between 350 and 500 (2%). That risk increases fourfold for someone with viral load between 7,000 and 20,000 and a CD4 count above 350 (to 8.1%), and reaches 42.9% when the viral load goes above 55,000 copies (See Viral load: predicting prognosis with viral load for more detailed information about disease progression risks).

Fourthly, people with higher CD4 counts may have a better chance of sustaining a virological response to treatment. Data from over 588 people commencing antiretroviral therapy in the Frankfurt Cohort found that a baseline CD4 count below 20 was associated with an increased risk of viral rebound. In addition, the greater a person's CD4 rise, the less likely they were to experience viral rebound. Surprisingly, this study did not find baseline viral load nor prior treatment to be associated with viral rebound. Two recent studies have also reported that people who are treated early, at a higher CD4 count, have a better chance of sustained virological suppression (Moore; Meibohm).

Another recent study found that starting treatment early (either by viral load or CD4 count) was advantageous. According to researchers from the John Hopkins University who retrospectively investigated the impact of highly active antiretroviral therapy on 553 patients, people who started therapy when their CD4 count was above 350 or their viral load was below 25,000 had significantly higher rates of initial and durable response to treatment. Durable response (defined as a viral load below 1000 in the long-term) occurred among 39% of patients who started treatment with a CD4 above 350, compared with 29% and 19% of those with CD4 count between 200-350 and below 200, respectively. When durable response was analysed by baseline viral load, 36% of those with a viral load below 25,000, 23% between 25,000-100,000 and 16% above 100,000 had sustained a very low viral load (Chaissson 2000).

One of the key arguments in favour of early treatment is that it is associated with better treatment outcomes. The three factors listed above - lower viral load, higher CD4 count, and treatment during the very early stages of infection - have all been associated with a better virological response to treatment (Yerly 2000).

Finally, there is some evidence to suggest that when HIV-positive men and women are matched for CD4 count, women will usually have lower viral load. This finding (in several large cohorts) has led to suggestions that women should start therapy at lower viral load and/or higher CD4 counts than men. This topic is discussed in more detail in Predicting prognosis with viral load in Viral load, CD4 counts and other tests.

The shift away from early treatment

When combination therapy was introduced there was a strong push to hit hard, hit early to prevent damage to the immune system and the illnesses that follow.

However, over the last five years, the pendulum has swung away from early treatment in the asymptomatic phase of HIV infection, for several reasons:

• growing concern about the long-term toxicities of HAART

• discouraging findings relating to our ability to eradicate HIV infection using current treatment strategies

• the clinical benefits of treatment begun before the onset of advanced disease remain unproven

• preliminary evidence from several large studies which shows no advantage to starting treatment with a CD4 count above 350 compared with starting treatment with a CD4 count between 200-350.

During early 2001, revised US and British guidelines moved away from early treatment strategies in people with chronic infection. See Anti-HIV therapy: Guidelines.

References

Chaisson RE et al. Association of initial CD4 cell count and viral load with response to highly active antiretroviral therapy - research letter. Journal of the American Medical Association 284(24): 3128-3129, 2000.

Meibohm A et al. Early versus late initiation of indinavir (IDV) in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-1-infected adults. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 521, 2000.

Paredes R et al. Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: Results from the EuroSIDA study. Archives of Internal Medicine 160(8): 1123-1132, 2000.

Yerly S et al. Time of initiation of antiretroviral therapy: impact of HIV-1 viraemia. The Swiss HIV Cohort Study. AIDS 14(3): 243-249, 2000.