CD4 cell count rise without undetectable virus

Immune reconstitution may occur among people on antiretroviral therapy who do not achieve 'undetectable' viral load. This type of discordant response is most common among heavily pre-treated individuals who are unable to fully suppress HIV but still experience improved health due to CD4 cell count recovery .

Delayed disease progression despite viral rebound

People who have a significant CD4 cell count rise in the absence of undetectable virus are less likely to develop an AIDS-related illness than people who have no response to treatment. For example, doctors in San Francisco found that people who failed to achieve or maintain 'undetectable' viral load with antiretroviral therapy still experienced CD4 cell count increases and were at very low risk of developing opportunistic infections. For patients with virological failure, risk of clinical progression was 18% at two years and 41% at four years (Deeks 2002).

Two large retrospective studies have reported that CD4 cell count is the key marker for predicting disease progression, at least in the short to medium term. The absence of a CD4 cell count rise, even in people with viral suppression, was associated with disease progression. In contrast, those who experienced a CD4 cell count increase showed improved immune function and delayed progression (Grabar 2000; Sabin 2000).

A French team has also found that immunologic responders do better than non-responders in terms of disease progression, but not as well as complete responders (Piketty 2000). Their risk of illness or death was sevenfold higher than that of immunologic responders with undetectable viral load. Nineteen per cent of patients had a significant increase in CD4 cell count despite viral load remaining above 500 copies/ml throughout the first twelve months of follow-up, but after an average of 30 months follow-up this group had CD4 cell counts nearly 100 cells/mm³ lower than those with undetectable viral load.

It seems that many individuals with viral rebound continue to experience immune benefit if they stay on antiretroviral therapy. For example, researchers reported that the average CD4 cell count remained 100 cells/mm³ above baseline two years after viral rebound while Canadian researchers reported that 6% of patients had a CD4 cell count increase of at least 50 cells/mm³ in the absence of a 1 log₁₀ drop in viral load after one year of antiretroviral therapy (Chaisson 2001; Wood 2002). French researchers found that people with viral rebound after four months of treatment had a lower rate of CD4 cell count increase (Le Moing 2002).

Disease progression in people with CD4 cell counts below 50 cells/mm³ is associated with the number of antiretrovirals being taken, with people taking five or more agents at 82% lower risk of further illness than death than people taking none at all. For further details of this study see Choosing a salvage regimen in Anti-HIV therapy: Changing treatment.

Reduced replicative capacity, or viral fitness, is also associated with sustained CD4 cell count gains in people with viral rebound. This is an expanding avenue of research; see Viral fitness, drug resistance and the immune system in Anti-HIV therapy: Restoring the immune system for further details.

There is also a secondary benefit of treatment among those with detectable virus. The Swiss Cohort study group reported that CD4 cell count depletion among those people with detectable virus is slower than among individuals not on treatment (Kaufmann 1998). However, it is important to note that this study reached its estimate of the speed of CD4 cell count decline after having excluded deaths, patients lost to follow-up and patients who opted to start a salvage therapy regimen - in all, around 25% of the cohort.

In total, these studies are grounds for cautious optimism for those people who fail to fully suppress HIV. While 'undetectable' viral load may be optimal to avoid drug resistance and improve CD4 levels, it is still possible to achieve substantial immunological benefits with a lesser degree of viral suppression, at least in the short term (Deeks 2000, 2002).

On the other hand, it is argued that the observed discordance between viral load response and CD4 cell count is unlikely to be sustained over the long-term. A Chicago-based clinical cohort of 111 treated patients, which compared changes in viral load and CD4 cell counts over 54 weeks, reported larger rises in CD4 cell counts in those whose viral load fell below 500 copies/ml than in those with a plateau above 500 copies/ml. With longer follow-up to 72 weeks, there was a downward trend in CD4 cell counts in those whose viral load had plateaued (Tenorio 1999). This suggests that a CD4 cell count rise in the absence of viral suppression will fade with time.

Falling viral load and falling CD4 cell counts

Some people achieve undetectable viral load on treatment but their CD4 cell counts continue to fall. One study found 13% of over 300 people on treatment experienced substantial viral load reductions as well as falls in CD4 cell counts (Maggiolo 1999). Canadian research has found that a fall in both CD4 count and viral load was the most common discordant response, occurring among 13% of 562 trial participants. High baseline CD4 cell count was associated with this type of response to treatment (Montaner 1999).

British researchers reported that 10% of 227 people who achieved a viral load below 400 copies/ml with their first anti-HIV combination also had a fall in their CD4 cell count at twelve months (Sullivan 1999).

While people who have a fall in CD4 cell counts despite full viral suppression are more likely to experience disease progression than people who get a boost in CD4 T-cells on top of undetectable viral load, there is evidence that those with viral suppression alone have a better short-term prognosis than complete non-responders (Piketty 2001).

Undetectable viral load without CD4 cell count rise

A number of studies show that over a third of patients receiving antiretroviral therapy for long periods may experience persistently low CD4 cell counts. Investigators at Chelsea and Westminster Hospital in London reviewed the records of over 1140 patients and found that after one year 16% failed to show an increase in CD4 cell counts above 50 cells/mm³ despite suppressed viral loads (Tung 2005).

However of those patients, 47% did experience an increase of more than 50 cells/mm³ after a further year of treatment, suggesting that discordant CD4 cell count responses with viral load may be transient in many patients. Importantly, they showed that patients who had a rise of at least 50 cells/mm³ by the first year of therapy were less likely to progress to AIDS or death over the second year.

Research at the Royal Free and University Medical School backs this up. Of 16,500 patients from the United Kingdom Collaborative HIV Cohort (UK CHIC) study, 1205 patients had undetectable viral loads four to eight months after starting antiretroviral therapy. Of these, 41% did not experience a rise in CD4 cell counts of greater than 100 cells/mm³. This proportion of patients gradually fell over the remainder of the first year confirming that discordant CD4 cell count responses are transient in many patients, but they did not find a relationship between a discordant CD4 cell count and progression to AIDS (Rider 2005).

An analysis of the EuroSIDA cohort found that poor CD4 cell count responses to treatment are frequent in individuals with low baseline CD4 cell counts and older age. Twenty-nine per cent of 780 patients analysed had CD4 cell count gains of less than 100 cells/mm³ in the first year of treatment, with a baseline CD4 cell count below 350 cells/mm³. A lower viral load at baseline and older age were associated with poorer immune reconstitution (Florence 2003).

Investigators in Paris found that between 5 and 27% of patients had low CD4 cell counts after prolonged use of antiretrovirals and successful viral suppression (Benveniste 2005). To try to understand this more the researchers identified 19 adult case patients with viral loads below 200 copies/ml for over a year, but with CD4 cell counts remaining below 250 cells/mm³. Compared with control patients who had CD4 counts above 500 cells/mm³ the case patients had fewer naive CD4 T-cells and lower thymic output. They also had elevated levels of cell death by apoptosis compared to controls.

The investigators concluded that the population of T-cells most impaired in these patients were naive T-cells, which suggests the reason for their lack of CD4 T-cells was impaired thymic function. They also suggested that increased immune activation in these patients may contribute to raised levels of apoptosis. It has been suggested that decreased levels of the cytokine interleukin-7 (IL-7) in patients starting antiretroviral therapy may be related to lack of thymic activity which could cause poor CD4 cell count responses (Ruiz-Mateos 2003). It seems some patients may not be able to produce enough IL-7 which is thought to help regenerate new CD4 T-cells. Consequently, CD4 cell counts do not increase.

Mechanisms causing discordant responses

At the 1999 San Diego Resistance Workshop important new insights on discordant responses were presented.

Dr Steve Deeks of the University of San Francisco investigated whether increased CD4 T-cell production or longer survival of CD4 T-cells can explain discordant responses. He found little difference between untreated patients, virological responders and virologic non-responders in CD4 T-cell production, implying that CD4 T-cell survival may be improved in those on treatment. In all cases, the individuals with discordant responses had been receiving protease inhibitor (PI) therapy. It has been suggested that PIs may extend CD4 half-life over time because they reduce rates of CD4 cell apoptosis independently of any anti-HIV effect. This explanation merits further investigation, particularly if there is a difference in the rate of discordant CD4 cell count and viral load responses in those in whom PIs fail and those in whom non-nucleoside reverse transcriptase inhibitors (NNRTIs) fail. However, it is worth bearing in mind that the cohorts discussed above demonstrate that people with sustained undetectable viral load enjoy the best immunological responses over time, suggesting that viral suppression is the prime mechanism of immune reconstitution and preservation.

Subsequent research by a Chicago group suggests that people who achieve undetectable viral load on PI therapy have the lowest rates of CD4 T-cell apoptosis when compared to non-responders (Pitrak 2001).

However, there is other evidence that extended CD4 T-cell survival does not explain CD4 cell count rises. Marc Hellerstein's team found that whilst CD4 T-cell survival declines dramatically during the first twelve weeks of therapy, it improves to levels seen in uninfected individuals after twelve to 18 months on therapy. Even in individuals with rising viral load at this time point, CD4 T-cell survival times are still within the range for uninfected individuals. A French team led by Denise Lecossier also found that improved CD4 cell counts in individuals with virologic failure were associated with increased thymic output rather than extended CD4 T-cell life. These researchers suggested that resistant virus is less damaging to the thymus, possibly because it replicates more slowly.

The 'thymic theory' suggests that the sharp increase in CD4 cell counts seen during the first months of therapy is unrelated to improved CD4 T-cell survival, and is instead a function of increased CD4 T-cell production. However, later in the course of therapy, CD4 T-cell production returns to rates similar to those seen in uninfected individuals, and CD4 cell count increases are more readily attributable to improved survival times for CD4 T-cells.

Another group of researchers has suggested that the rate of CD4 T-cell reconstitution during the first two months of treatment reflects the previous rate of CD4 cell count decline. That is, if a person has not had CD4 cell count decline before starting treatment, they will have little increase, despite suppression of viral load. After that initial two-month period, the main determinant of CD4 cell count response is the extent of viral load suppression. These factors, they argue, explain paradoxical CD4 cell count and viral load responses to treatment (Renaud 1999).

Another group has suggested that immune activation and strong HIV-specific CD4 and CD8 T-cell responses may explain discordant responses where CD4 cell counts remain stable despite long periods of detectable viral loads (Sufka 2002). However, research by a French group suggest that using a steroid agent to reduce immune activation paradoxically worsens the rate of CD4 T-cell apoptosis despite undetectable viral load (Roger 2004).

Finally, a study of patients with viral load below 50 copies/ml on antiretroviral therapy that used a viral load assay with a detection limit of 3 copies/ml found that those who experienced viral blips during the follow-up period had significantly lower CD4 cell counts after twelve and 18 months (Marcelin 2004).

For further discussion of discordant virological and immunological responses to treatment, see Viral fitness, drug resistance and the immune system in Anti-HIV therapy: Restoring the immune system.

Key research

Deeks conducted a clinic-based, observational study of HIV-infected individuals who commenced PI-based triple therapy in December 1997. 302/485 people had viral rebound above 500. 55 clinical events occurred in 567 person years. Probability of progression at two years was 18%, and 41% at four years. Progression was associated with viral load which returned within 0.4 log of baseline and low pre-therapy CD4 nadir.

Katlama reported on three groups of patients: VL < 10,000 (n=24), VL>10,000 (n=14) and vL<20 copies/ml (n=29) for at least 18 months. Patients with viral load < 10,000 copies/ml had significantly stronger HIV-specific CD4 and CD8 responses than other groups, and relatively stable CD4 cell counts over the follow-up period.

Sufka recruited three groups of patients receiving current PI-based therapy who had a CD4 cell count below 50 cells/mm3 and/or viral load above 50,000 copies/ml prior to commencing HAART. Participants were divided into three groups: treatment success group (VL< 50 copies/ml and CD4 cell count > 200 cells/mm3 for at least two years); discordant response group (VL between 500 and 5,000 copies/ml and CD4 count >200 cells/mm3 with stable or increasing trend for at least two years); and treatment failure group (viral load > 400 copies/ml and increasing after initial reduction of at least 3 log, and CD4 cell count declining). Ten patients were enrolled to each group. Patients with a discordant response to treatment had significantly greater CD8+ and CD4+ T-cell responses to HIVs gag antigen (P=0.03), showing a stronger HIV-specific immune response among this group. Patients in the discordant group were also more likely to have non-cytolytic CD8 cell-mediated suppressive activity targeted at CXCR4-tropic virus, although this difference was not statistically significant. Patients in the discordant group also had higher levels of immune activation as measured by circulating CD4 and CD8 cells (p=0.005 and 0.001 respectively) than individuals with virologic suppression.

Chaisson studied 515 people who achieved at least one viral load result below 500 while taking their first HAART regimen. Participants were divided into four groups: group 1- sustained viral suppression below 1000; group 2a - viral rebound above 1000 but then re-suppression below 400; group 2b - sustained viral rebound but HAART continued; group 3 - rebound and HAART discontinued. Median CD4 rises at six, 12, 18 and 24 months were: group 1 +81, 141,174, 200; group 2a +66, 96, 105, 123; group 2b +76, 99, 116, 116; group 3 +78, 79, 69, 41.

Piketty reported that 150 NRTI-experienced individuals taking indinavir plus NRTIs were followed for a median of 30.7 months. At baseline, median CD4 count was 73 and viral load was approximately 50,000 copies/ml. During follow-up, median CD4 increase was 294 and 79% achieved a CD4 rise of over 200. The median reduction in viral load was 1.5 log and 60% achieved a viral load below 500. Virologic response was defined as greater than a one log reduction below 50 copies/ml and immunologic response was defined as an increase of over 100 cells/mm3. AIDS events for virologic (V+) and immunologic (I+) responses were as follows at 30 months: 2% V+ and I+; 14% V+ and I-; 21%V- and I+; 67% V- and I-. Younger age was associated with a better response. V+I- was associated with a relative risk of progression of 13.3 compared with complete responders. V-I+ had a 6.9 risk of progression compared with complete responders but V-I+ had significantly less chance of progression than non-responders. This study suggests immunologic response may be a more important predictor of progression in patients with discordant responses to treatment.

Sabin studied the clinical implications of a discordant CD4/viral load response to HAART in 965 individuals attending a Frankfurt clinic from July 1994-Jan 1999. Virological response (fall of at least one log) without a CD4 rise occurred in 22% of patients, whereas 9.1% had a CD4 increase but no drop in viral load. Median follow-up was 23 months. During this time, 48 people developed AIDS and 18 died. Poor CD4 response, regardless of viral load, was associated with faster disease progression.

Grabar presented one of the largest analyses so far of discordant outcomes, in which 2,236 protease inhibitor (PI) naive patients began a new regimen including a PI with two NRTIs. Patients were classified as virologic responders if they sustained a fall in viral load to below 1,000 copies or 1 log below baseline, and immunological responders if their CD4 count rose by at least 50 cells. After six months, almost half the cohort were both virologic and immunologic responders; 16% were non-responders; 17% were immunological but not virological responders; and 19% had a virologic but not an immunologic response. Non-responders were 2.8 times more likely to progress clinically to a new AIDS-defining event or death than responders. Those with a virologic response but no immunologic response were 1.6 times more likely to do so. However, there was no difference in the risk of disease progression in the group with an immunologic response but no virologic response, suggesting that the rise in CD4 is an important independent sign of treatment benefit.

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