Researchers have recently begun to turn their attention to the question of whether the speed of viral load suppression makes any difference to the long-term risk of treatment failure.

The question has arisen as a result of an observation from the Amsterdam Duration of Antiretroviral Medication (ADAM) study of induction and maintenance treatment. This study tested whether a period of intense four-drug therapy followed by stepping down to a two-drug regimen could maintain long-term viral load suppression. Researchers found that people with the fastest decline in viral load on four drugs were most likely to maintain viral load below 50 copies/ml when switched to a two-drug maintenance regimen (Reijers 1998).

See Induction and maintenance therapy in Anti-HIV therapy: Choosing your treatment strategy for further discussion of this topic

The rationale for ultra-rapid suppression

HIV's life-cycle is very short, and new generations of HIV are emerging every day. This means that the longer the delay in suppressing virus replication, the greater the chance that a drug resistant mutant will emerge which can form the basis of a drug resistant virus population.

In addition, the faster a person achieves undetectable viral load, the more likely they are to sustain long-term viral suppression. The level of viral load after four weeks of treatment strongly predicts a person's chance of having undetectable viral load at week 24, although viral load reductions at both time points are strongly influenced by the level of viral load at baseline (Smith 2004).

Although it is clear that the faster viral load declines the better, it is unclear what factors affect the rate of viral decline. One strategy is to reduce viral load rapidly by using a very powerful combination, possibly using five or more drugs. However, it is uncertain whether this approach will produce superior virological outcomes, for some of the reasons discussed below. One study found that people who received five drugs as initial therapy achieved a viral load below 50 copies/ml much more quickly than those who received three drugs - a median of four weeks compared to 12 weeks. However, there was no difference between the two regimens in the rate of viral decay during the first two weeks of treatment. These findings call into question theories about the rate of viral decline. Patients in similar studies need to be followed up over a much longer period to be certain that five drugs are as well tolerated as three or four drugs, and that fast suppression of viral load correlates with less long-term risk of treatment failure and drug resistance.

The speed of viral load suppression has also been proposed as a rapid surrogate for evaluating the efficacy of new antiretrovirals. American researchers investigated the possibility of using the decline in HIV viral load immediately following the commencement of antiretroviral therapy as a predictor of treatment efficacy. HIV dynamics were assessed by the measurement of daily samples during the first six days of therapy.

The 124 HIV-infected participants in the study were drawn from three clinical trials of combination antiretroviral therapy or protease inhibitor monotherapy. In all three trials, frequent blood samples had been taken, allowing the intensive study of viral dynamics over the first twelve weeks of treatment.

The investigators divided the participants into good and poor responders. Good responders were people who had a continuously decreasing viral load over twelve weeks and also had their HIV viral load fall by greater than 1.5log₁₀ or to below 50 copies/ml. Mean change in HIV viral load for poor responders at weeks 4 and 8 was 0.82 and 0.5 log₁₀. In contrast, good responders had average viral load falls of 2.10 and 2.60log₁₀ at weeks 4 and 8, respectively.

The authors calculated individual rates of viral decay from blood samples collected during the first six days of treatment. Viral decay rate constants at day 6 were significantly correlated with changes in HIV viral load at weeks 4, 8 and 12. The viral decay rate which divided good and bad responders was 0.21log₁₀ per day.

A decay rate constant of less than 0.16 log₁₀ per day at day 6 was overwhelmingly associated with a poor response, whereas more than 95% of people with a decay constant above 0.28 log₁₀ were good responders. Logistic regression analysis showed that twelve-week response rates can be predicted for 84% of people based on the initial viral decay rates for days 0 to 6.

The authors concluded that two viral load measurements conducted on days 3 to 5 and day 6 can provide a very early assessment of drug efficacy and be used as an accurate predictor of longer-term response to treatment (Polis 2001).

Drug mechanisms

Drugs differ in the speed at which they begin to exert an antiretroviral effect. Protease inhibitors and nucleotide reverse transcriptase inhibitors begin to exert an effect immediately upon absorption because they do not have to go through a stage called phosphorylation. In contrast, nucleoside analogue reverse transcriptase inhibitors (NRTIs) must be phosphorylated, which means they do not take effect immediately. However, this delay is relatively short, and what contribution it might make to the emergence of drug-resistant mutants is difficult to quantify. See Choosing a nucleoside or nucleotide reverse transcriptase inhibitor backbone in Anti-HIV therapy: Choosing a combination for an explanation of phosphorylation.

Drug concentrations may be a crucial factor in the rate of viral decline. Dutch researchers found that blood levels of nelfinavir or saquinavir (Invirase / Fortovase) during the first two weeks of treatment were critically associated with the speed of viral load decline in patients receiving a quadruple combination of nelfinavir, saquinavir, d4T (stavudine, Zerit) and 3TC. The team suggested that more work needed to be done to calculate the average drug concentrations during the first few weeks of treatment, and to develop methods to ensure that patients have the appropriate drug levels during what researchers consider to be the most critical period of therapy (Hoetelmans 1998).

Impact of cell types on suppression

Viral replication in different cell types may be shut down at different rates because drugs differ in their ability to penetrate into different cell types. This may complicate attempts to measure antiviral effect during the early weeks of treatment.

If the combination used does not have the capacity to penetrate all known cell types infected by HIV, the combination will not exert a uniform effect in all the cells of the body. For example, protease inhibitors may not always reach adequate levels in semen because they bind easily to protein in the blood. As a result, full viral suppression may not be achieved, and sub-optimal drug levels may act as a spur to the development of drug-resistant virus in this compartment.

Research has also shown that the classes of drugs vary in their capacity to reduce viral replication in the lymph nodes, one of the main reservoirs of viral activity in the body. A study of twelve patients with viral suppression below 20 copies/ml for an average of 25 months revealed that three out of five of those who had received only NRTIs still had significant evidence of virus production in their lymph nodes, compared to one out of seven of those who had also received protease inhibitor treatment. The remaining protease inhibitor-treated individuals had no evidence of virus production in the lymph nodes and also showed evidence of lymph node regeneration, as formerly damaged tissue was restored to healthy working order (Ruiz 1999).

A group from California has presented preliminary information from a small study investigating the effects of therapy on residual viral reservoirs. Six participants in the Merck 035 study of indinavir, AZT and 3TC underwent lymph node biopsies one year and two years after starting treatment. All had sustained viral load below 50 copies/ml for two years. Those whose viral load fell below 50 copies/ml fastest did not experience evolution in RNA sequences from lymph node tissue, which suggests this pool was not subject to ongoing replication. Significant evolution was seen in those patients whose viral load fell more slowly, or who experienced bursts of viraemia whilst on treatment (Gunthard 1999).

Gender differences in speed of viral load suppression

A review of 378 patients at the Royal Free Hospital in London has shown that after controlling for baseline viral load, women were more likely to achieve a viral load below 500 copies/ml within 16 weeks of commencing highly active antiretroviral therapy (HAART; Moore 2001).

References

Gunthard H et al. Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy. J Virol 73: 9404-9412, 1999.

Hoetelmans RMW et al. The effect of plasma drug concentrations on HIV-1 clearance rate in anti-retroviral naive patients during a quadruple drug regimen. AIDS 12: F111-F115, 1998.

Moore AL et al. Gender differences in virologic response to treatment in an HIV-positive population: a cohort study. J Aqcuir Immune Defic Syndr 26: 159-163, 2001.

Polis MA et al. Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet 358: 1760-1765, 2001.

Reijers MH et al. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet 352: 185-190, 1998.

Ruiz L et al. Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue. AIDS 13: F1-F8, 1999.

Smith CJ et al Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals. J Acquir Immune Defic Syndr 37: 1155-1159, 2004.

Weverling GJ et al. Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy. AIDS 12: F117-F122, 1998.