Researchers in the province of British Columbia (BC) reviewed information in their database on more than 1,200 PHAs. The data was collected between August 1996 and September 1999. The research team was examining data to find the effect of HAART on survival. In analysing their data the researchers took into account the following factors which might have had an impact on survival:

• a diagnosis of AIDS
• protease inhibitor (PI) use
• age
• gender
• CD4+ cell count
• viral load

According to their calculations, which analysed these factors together, the CD4+ count at which subjects started therapy was the only significant factor linked to their subsequent survival.

Study details

Researchers enrolled 1,219 subjects who had never used anti-HIV therapy and who had the following profile at the start of this study:

• 15% female, 85% male
• average age – 37 years
• average CD4+ count – 280 cells
• average viral load – 120,000 copies
• 13% had AIDS

On average, subjects were monitored for about 2.3 years. The most commonly prescribed combinations of anti-HIV drugs were as follows:

• d4T (Zerit, stavudine), 3TC (lamivudine, Epivir) and indinavir (Crixivan)
• AZT (Retrovir), 3TC and indinavir
• d4T, 3TC and nevirapine (Viramune)

Results – Survival

Over the course of the study, 104 subjects died. The proportion of these deaths that was due to HIV was about 79%.

Readers should note that the criteria for access to HAART were relaxed one year after the study started — in July 1997. In practical terms this meant that subjects who used HAART during the first year of the study had the following profile:

• high viral loads — averaging 170,000 copies
• nearly twice as likely to have AIDS compared to subjects who entered the study after July 1997
• very likely to have a protease inhibitor prescribed as part of their regimen

Survival and CD4+ cell counts

In focusing on survival, researchers divided subjects into the following three groups based on their CD4+ cell counts at the start of the study:

• fewer than 50 cells – 12% of subjects
• between 50 and 199 cells – 25% of subjects
• 200 or more cells – 64% of subjects

(Note: percentages do not total 100 because of rounding)

The proportion of subjects who died after one year in each group was as follows:

• fewer than 50 cells – 9% died
• between 50 and 199 cells – 6% died
• 200 or more cells – 1% died

These differences in death rates were statistically significant.

Survival and viral load

The researchers also divided subjects into the following groups based on their viral load at the start of the study:

• fewer than 100,000 copies
• 100,000 copies or greater

The rates of death for subjects in each of these two groups were as follows:

• fewer than 100,000 copies – 2%
• 100,000 copies or greater – 4%

These differences in death rates were statistically significant.

The big question

Which factor was most associated with survival? In an initial analysis researchers found that those PHAs who had one of the following factors before they started therapy had an increased risk of death:

• using a protease inhibitor
• previous diagnosis of AIDS

When researchers re-analysed the data (called a multivariate analysis), taking into account several factors — CD4+ cell count, viral load, use of PIs — they found that only one factor remained statistically significant:

• CD4+ count at the start of the study

The risk of death

Using this analysis that accounted for several factors the researchers calculated the risk of death as follows:

• Subjects who started therapy when they had fewer than 50 CD4+ cells were nearly seven times more likely to die than subjects who had at least 200 CD4+ cells.
• Subjects who began therapy with a CD4+ count between 50 and 199 cells were three times more likely to die than subjects who started therapy when they had at least 200 CD4+ cells.

These differences were statistically significant.

The risk of developing AIDS or dying

By the end of the study, the following events had occurred:

• 25 subjects developed AIDS
• 57 subjects died

The researchers calculated the risk of subjects developing AIDS or dying from the time they began to use HAART and came up with the following results:

• Subjects who began therapy when they had fewer than 50 CD4+ cells were about eight times more likely to develop AIDS or die than subjects who started therapy when they had at least 200 cells.
• Subjects who began therapy when their CD4+ count ranged between 50 and 199 cells were five times more likely to develop AIDS or die compared to subjects who started therapy when they had at least 200 cells.

Important issues

1. In this study, most deaths occurred in PHAs who had fewer than 200 CD4+ cells. At first there appeared to be a higher number of deaths among people who used a PI. This occurred because PHAs who initially received PIs were considered to be in poor health and at high risk for developing AIDS or dying by their doctors. But when researchers recalculated the risks, taking into account several factors such as CD4+ cell counts, age, sex, viral load and PI use, only the CD4+ cell count at the start of therapy was associated with subsequent survival.

2. While this study does not reveal the best time to begin therapy, it provides other important information, namely:

• If therapy is started below a "critical threshold" — a CD4+ cell count of 200 cells — then the benefit(s) of HAART are reduced.
• Delaying therapy when there are less than 200 CD4+ cells greatly increases the risk of developing AIDS or dying.

• 85% of men who had fewer than 200 CD4+ cells and viral loads greater than 110,000 copies who did not use anti-HIV drugs would develop a life-threatening infection or die within 2.3 years.

This point is noteworthy because in the BC study, of those subjects with a similar profile who received treatment, only 22% developed AIDS or died.

Points to consider:

1. The research team notes that when monitoring PHAs who have not yet started HAART, the emphasis should be on CD4+ cell counts.

2. If PHAs are going to start therapy it should be initiated before their CD4+ cell count falls below the 200 cell mark.

3. Although the best point in the course of HIV disease to start therapy is still not clear, this study does provide valuable information about the risks of delaying therapy, particularly at low CD4+ cell counts. This information should be useful for those who counsel PHAs about the timing of therapy.

REFERENCES

1. Hogg RS, Yip B, Chan KJ, et al. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA2001;286(20):2568-2577.

2. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4 + lymphocytes as prognostic markers of HIV-1 infection. Annals of Internal Medicine1997;126:946-954.

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