Sweet relief

[keyite]

Went to see my HIV doc today and really was preparing for the worst. It has been (or at least felt like) a steep slide downwards ever since diagnosis - CD4 downwards, VL upwards. I was expecting having to discuss going onto meds this visit, since I don't really want CD4 to go much below 350.

I think she probably sensed my anxiety when I walked in and she gave me a big smile and told me it was good news. CD4 slightly up, VL very much down. CD4% dropped a bit, but not below where it has been before (details in the signature).

Phew... My sense of relief must have been palpable. Even if it only buys me another six months off meds then it definitely is a very welcome result. And good enough that she felt I could now move to three-monthly rather than two-monthly monitoring.

These visits are so tough but she really makes it much easier, even when it's been bad news. Right from the beginning, I felt her concern was absolutely genuine and never a shadow of a doubt that she has my best interests at heart. Plus she's just a really lovely woman. If I wasn't gay I'd want to marry her! 

[Andy Velez]

Sweet relief indeed. That's excellent news. And it sounds like you have a doctor who's sensitive to your feelings which is another very good plus.

Just keep trucking and taking good care of yourself.

Cheers,

[Tempeboy]

Well done. what's your secret?

[Iggy]

Good deal so far.  Very similar situation as far as numbers right now.

Here's to another 6 months!

[keyite]

Thanks guys, means a lot. No secret. Or rather, if I knew what it was, trust me, I'd be piling it on!

[Central79]

Hey Key

Congratulations on the good result. I'm really pleased for you - I hope you manage to dodge meds for a while to come.

Also, it's great that you have a doctor you trust and get on with. I wish I did! I may well change when I get close to needing the pills.

Hope you're having a good w/e.

M x.

[Longislander]

good for you! keep up the good work, here's to another year!! 

[Tempeboy]

Hey Key,

Had this sent to me today by a friend.  He has been reluctant to start, and found this motivating.  It might not apply to you but others might find it helpful.

ABSTRACT
Background: The increase in CD4 count may reach a plateau after some duration of virological response to highly active antiretroviral therapy (HAART).

Methods: A total of 1281 HIV-infected patients initiating HAART were enrolled in the AntiPROtease (APROCO) cohort. We investigated determinants of increase in CD4 count using longitudinal mixed models in patients who maintained a plasma HIV RNA <500 HIV-1 RNA copies/mL.

Results: A total of 870 patients had a virological response at month 4. The median follow-up time was 57 months. Mean estimated increases in CD4 count in patients with persistent virological response were 29.9 cells/N<L/month before month 4, 6.4 cells/N<L/month between months 4 and 36, and 0.7 cells/N<L/month (not significantly different from 0) after month 36. Three factors were associated with a significantly positive CD4 count slope after month 36: male gender (+0.9), no history of antiretroviral therapy at baseline (+1.7) and baseline CD4 count <100 cells/N<L (+2.6). In patients who maintained a virological response after 5 years of HAART, a CD4 count >500 cells/N<L was achieved in 83% of those with a baseline CD4 count b %200 cells/N<L and in 45% of those with a baseline CD4 count <200 cells/N<L.

Introduction
The main objective of long-term antiretroviral therapy is to reach and maintain a sufficiently high CD4 cell count to provide the patient with long-term protection against opportunistic infections and cancers. We and others [1-3] have shown that the magnitude and duration of the increase in CD4 cell count are mainly driven by the achievement and maintenance of a complete virological response, characterized by a very low level of residual plasma HIV RNA; that is, in routine clinical practice, a viral load under 500 HIV-1 RNA copies/mL, the detection threshold of the less sensitive arrays used to quantify HIV RNA.

The length of time for which the CD4 cell count continues to increase in those patients who maintain a complete virological response is, however, a matter of debate. Some authors have suggested that, after 2 to 3 years of virologically successful therapy, the increase slows down and CD4 cell counts may reach a plateau in most patients [4-7]. Others have shown a continuous and vigorous increase in the third year of complete virological response and thereafter [8-10]. Discrepancies between studies may be a result of insufficient follow up, an insufficient number of patients or inadequate modelling of data. Moreover, in these previous studies, the influence of the degree of previous immunodepression and of other cofactors known or thought to modify immune restoration, such as age [11], gender [12] and treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) [12-14], was not explored. To gain more understanding of the history of CD4 cell reconstitution and factors related to long-term antiretroviral treatment-mediated CD4 cell count increase, we studied the long-term evolution of CD4 cell count in a large prospective cohort of treated patients.

More specifically, we investigated whether there is a plateau of CD4 cell count in patients in whom a complete virological response is maintained and, if such a plateau exists, at what time the slope of CD4 cell count becomes zero and whether the plateau is observed in every category of patients, especially in those who initiate potent antiretroviral therapy while their CD4 cell count is very low.

Patients and methods
The APROCO/COPILOTE cohort study (ANRS C08) has been described in detail elsewhere [15]. Briefly, the cohort enrolled 1281 HIV-l-infected patients in 47 centres in France in 1997-1999 at the initiation of a protease inhibitor (PI). Follow-up is ongoing and patients have a CD4+ cell count and a plasma HIV RNA measurement every 4 months. CD4+ cell counts are prospectively measured by standardized flow cytometry. All plasma HIV RNA levels are prospectively measured by the assay routinely available in each centre. Every modification of antiretroviral therapy is recorded.

For the current analyses, we selected patients with an early virological response, i.e. a plasma HIV RNA <500 copies/mL after 4 months of protease inhibitor (PI) therapy, and data were censored at the time of occurrence of virological rebound or the last follow-up visit recorded in the database or the 64-month visit, whichever occurred first. Virological rebound was defined as the first occurrence of a rise of plasma HIV RNA above 500 copies/mL. The slopes of CD4 cell count over time were estimated with linear mixed models, taking into account correlation between repeated measurements in the same individual. The change in CD4 cell count was first fitted by two slopes before and after month 4, and then we looked for inflexions of slopes over time after month 4. Secondly, the effect of explanatory variables on estimated slopes of CD4 cell count after month 4 was explored by testing interactions between fixed covariates and each of the slopes. Variables associated with at least one slope in univariate analysis with a P-value <0.25 were eligible for adjusted analysis. To take into account a switch from PI-based to abacavir- or NNRTI-based therapy, we added to the model an interaction term between the long-term slope and a time-dependent indicator of switch, which took a value of 0 at any time after month 4 and before the switch, as well as in patients who never switched therapy, and a value of 1 at the time of the switch and thereafter. For determining the most likely of change of slopes, models were compared using the Akaike information criterion. It should be noted that the higher the likelihood of the model, the lower the Akaike information criterion. Normality of distribution of residuals of the final multivariate model was graphically checked. In order to check if the inclusion of untransformed values of CD4 cell count in the models yielded skewed estimations, analyses were repeated with square root transformed values. All statistical analyses were performed using Statistical Analysis System software 8.2 (SAS Institute Inc., Cary, NC). For the computation of linear mixed models, we used the proc mixed procedure.

Results
Of the 1281 patients enrolled in the cohort, 870 (67.9%) had a plasma HIV RNA <500 copies/mL at the 4-month visit and were selected for the present study. Their baseline characteristics are described in Table 1. The median follow-up was 57 months (interquartile range 25-62 months). A rebound of plasma HIV RNA >500 copies/mL was observed in 438 patients (50.3%). Therefore, the median time with persistent virological suppression in the 870 patients was 33 months (interquartile range, 11-56). During this period of persistent response, 229 patients switched from a PI to a NNRTI (efavirenz, n=103; nevirapine, n=92) or abacavir (n=34) after a median duration of PI therapy of 23 months (interquartile range, 15-34). Median follow up after switch and before censoring was 26 months (interquartile range, 13-37). A total of 8708 measures of CD4 cell count between enrolment and virological rebound or censoring were recorded in the database. The median variation of CD4 cell count from baseline to month 60 in patients who maintained a complete virological response is displayed in Table 2 and in Fig. 1 for the whole cohort and in Table 2 and Fig. 2 according to baseline CD4 cell count. Briefly, median CD4 cell count did not vary much between months 36 and 60, except in patients who had a baseline CD4 cell count <100 cells/N<L, who still had a median rise of more than 100 cells/N<L during these 3 years. However, only 85% of patients who had a baseline CD4 cell count <100 cells/N<L had a CD4 cell count >200 cells/N<L at month 60 as compared with 97% for the whole cohort. Similarly, only 45% of patients who initiated PI therapy with a CD4 cell count <200 cells/N<L had a CD4 cell count >500 cells/N<L after 5 years of successful therapy as compared with 68% of patients who initiated PI therapy with a CD4 cell count between 200 and 350 cells/N<L and 90% of patients who initiated PI therapy with a CD4 cell count >350 cells/N<L.

We then looked for the most appropriate model for the evolution of CD4 cell count over time. The model associated with higher likelihood (lower Akaike information criterion) was a model including two changes of slope: at months 4 and 36 (Table 3). The estimated slopes were +29.9 cells/N<L/month before month 4, 4+6.6 cells/N<L/month between months 4 and 36 and +0.7 cells/N<L/month after month 36. This latter slope was not significantly different from 0 cells/N<L/month (P=0.12; 95% confidence interval -0.2, +1.5). The variance of random effects of the slope of CD4 cell count after month 36 was significantly different from 0 (P<0.0001), which indicated the persistence of important sources of variation and suggested that this late slope may be significantly positive in some subgroups of patients.

We thus studied the determinants of slopes between months 4 and 36 and after month 36. In unadjusted analyses (Table 4), five of the factors studied had a significant effect on the slope between months 4 and 36: (1) age at baseline, with patients younger than 50 years old having a higher slope of CD4 cell count (2.8 cells/N<L/month; P=0.0001) than other patients; (2) Centers for Disease Control and Prevention (CDC) stage at baseline, with patients at stage C having a higher slope than those at stage A or B (+1.8 cells/N<L/month; P=0.004); (3) baseline plasma HIV RNA, with patients with HIV RNA b %100 000 having a higher slope than those with <100 000 copies/mL (+2.4 cells/N<L/month; P<0.0001); (4) baseline CD4 cell count, with patients with <100 cells/N<L having a higher slope than those with b %100 cells/N<L (+1.8 cells/N<L/month; P=0.005); and (5) virological response at month 1, with those with a complete response, i.e. plasma HIV RNA <500, having a higher slope than those with b %500 copies/mL (+1.8 cells/N<L/month; P<0.001). In these unadjusted analyses, three factors were associated with a positive (>0 with a P-value <0.05) slope of CD4 cell count after month 36: (1) male gender [+0.9 cells/N<L/month; 95% confidence interval (CI) 0.04-1.9; P=0.04]; (2) being naC/ve to antiretroviral drugs at initiation of PI (+1.7 cells/N<L/month; 95% CI 0.5-2.9; P=0.004); and (3) having a baseline CD4 cell count <100 cells/N<L (+2.6 cells/N<L/month; 95% CI 0.7-4.4; P<0.01). In the model adjusted for the three factors associated with the slope after month 36 in unadjusted analyses, only two factors were still associated with the slope after month 36: male gender (+1.5 cells/N<L/month; 95% CI 0.2-3.0; P=0.02) and being naC/ve to antiretroviral therapy (+1.6 cells/N<L/month; 95% CI 0.7-4.4; P<0.01), while the effect of low baseline CD4 cell count was attenuated and became nonsignificantly different from 0 (+1.6 cells/N<L/month; 95% CI -0.4 to 3.7; P=0.11). When analyses were repeated using square root transformed values of CD4 cell counts, very similar results were produced by the models, with the slope after month 36 being nonsignificantly different from 0 in the whole population, and the slope after month 36 being significantly but slightly positive in patients with baseline CD4 counts <100 cells/N<L or who were antiretroviral naC/ve at baseline.

Discussion
We acknowledge that our study may be limited by insufficient power due to relatively low number of patients and/or insufficient follow-up after 36 months, especially in this particular strata of patients with low CD4+ cell counts at baseline because the APROCO cohort study enrolled mostly slightly immunosuppressed patients. Longer follow-up of the APROCO cohort and repeated analyses in larger databases are needed to confirm these findings. Nevertheless, observed data as well as the confidence interval of the unadjusted late slope of CD4+ cell count in this strata of patients with CD4+ cell count <100/mm3 before initiation of PI-containing regimen suggests that a potential late increase of CD4+ cell count in these patients would be less than 4.4 cells/mm3/month, i.e. quite low. Moreover, adjusted analyses suggested that the late increase of CD4+ cell count in this subgroup of patients may be partly explained by other factors, i.e. gender or naivete of antiretroviral drugs at the initiation of HAART. Consequently, even if such a small late increase exists, the majority of these patients will have to wait a very long time until their CD4+ cell count reaches a fully protective level.

It should be investigated if those patients initiating HAART with a very low CD4+ cell count might benefit from specific interventions such as more intensive antiretroviral therapy or early administration of interleukin 2. Another limit of the study is the restricted follow-up because of its censoring due to virological rebounds. This censoring may have biased the estimation of long-term slope. This bias may have been toward an overestimation of the CD4 increase because patients who were not censored and contributed to the estimation of this slope are those who responded to treatment better. However, among patients censored, the patients who had intermittent low-level viremia may have had a better immunological response than those analysed [9]. Because these "blippers" were probably far from the majority of those who had a virologic rebound in our cohort, we believe that such potential bias may not have strongly modified our conclusions.

A smaller increase of CD4+ cell counts in patients initiating HAART with a NNRTI compared to those initiating HAART with a PI has been evidenced in at least three observational studies [12-14], suggesting immunologic properties of PIs independent of their virologic potency. Our data suggest that such a differential immunologic effect of different HAART strategies may not be applicable to switch from PI to NNRTI and thus confirms that such a strategy of switch is not detrimental on an immunologic point of view which has not been shown previously in the context of routine care for such a long follow-up. Similarly, the smaller increase of CD4+ cell count observed during the first years of HAART in patients co-infected with Hepatitis C Virus [1,16,17] does not appear to have an impact on immune restoration after longer durations of treatment in patients who maintain a persistent virologic response.

The reason for such a plateauing of CD4 counts after 3 years of control of viral replication remains undetermined but is probably multifactorial. An explanation has been suggested for the lack of increase in CD4 cell count in a subset of patients initiating HAART at very low CD4 cell counts [18]. Reconstitution of CD4 cell count after the first few weeks of active antiretroviral therapy is principally a result of an increase in naC/ve CD4 cell count, and this increase in naC/ve CD4 cells depends on the pool of naC/ve cells present before initiation of HAART, which is very low in some patients who are very immunosuppressed when they initiate HAART. Conversely, for those patients who reach normal or almost normal CD4 cell counts, a further increase is of no use and probably unattainable. Residual low replication of HIV may also impede immune reconstitution in some patients. It has been shown that immune reconstitution in terms of increase in CD4 cell count and equilibrium between T-cell subsets is less complete in patients who have low residual detectable viral replication compared with patients in whom plasma HIV RNA is maintained at <20 copies/mL [19]. Because of the design of our observational study, in which plasma HIV RNA is measured using different assays across centres, we were not able to study the impact of low-level viral replication on the increase in CD4 cell count.

Our data thus confirm that the increase in CD4 cell count reaches a plateau after 3 years of complete virological response. Even if some patients still have an increase in CD4 cell count after 3 years, this increase appears to be small and is not sufficient to overcome the initial immune deficit in all patients who initiate antiretroviral therapy at a very low CD4 cell count. It has been suggested that this incomplete restoration of CD4 cell count despite virological suppression is accompanied by the persistence of functional defects in cellular and humoral immunity [5,20]. This incomplete immune restoration may have clinical consequences as only patients who restore a CD4 cell count >500 cells/N<L reach the same levels of mortality as the general population [21]. Every effort should thus be made to make antiretroviral therapy available to all HIV-infected patients sufficiently early to avoid the appearance of an irremediable immune deficit. Our data support the intuitive view that the initiation of antiretroviral therapy should not be delayed until the occurrence of a CD4 cell count <200 cells/N<L if the objective is to maintain every patient with a CD4 cell count >200 cells/N<L, which guarantees protection against most opportunistic infections. However, if the goal is to give the opportunity to almost all patients to reach a CD4 count of 500 cells/N<L, it may be preferable to initiate therapy before the occurrence of a CD4 cell count <350 cells/N<L.







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[Ann]

Tempeboy,

In future, could you please follow the guidelines found in the Research forum Welcome thread when posting articles.

Thank you for your cooperation.

Ann

[keyite]

Matt, Longislander - thanks guys, another year would be great, here's hoping!

Tempeboy - thanks for the article, this is exactly why I don't want CD4 to go much below 350 before starting HAART - my impression too is that CD4 ultimately recovers further the higher your CD4 was when initiating. But obviously this then has to be weighed with the toxicity and side effects of the meds, short-term and particularly long-term. The meds have undeniably got much, much better over the years, but I still think it's important to remember we've only had the current first-line meds for about a decade, some even less than that. Still, it isn't really that I'm afraid of starting HAART, more that I want to wait until I get the most 'bang for the buck' and, from what I gather, 350 is probably about right.