Consequences for the Further Course of Disease

In addition to the risk of death and disease progression, the controversy over the optimal time for starting therapy also raises other questions. Based on large cohorts, there have been repeated attempts to prove that the time point when therapy is started influences virological or immunological treatment success. The problems with such arguments are discussed below.

Is virological response less durable with a low CD4 cell count and a high viral load?

At first glance, many cohort studies have clearly demonstrated that virological response is poorer if the CD4 cell count at initiation of treatment was low and the viral load high (Casado 1998, Mocroft 1998 and 2000, Miller 1999, Wit 1999, Deeks 1999, Chaisson 2000, Grabar 2000, Le Moing 2002, Yamashita 2001, Palella 2003). In a meta-analysis of 30 prospective studies, baseline CD4 cell count was important for viral load decline on treatment (Skowron 2001). It might appear straightforward: the higher the viral load and the lower the CD4 count, the less the virological success of HAART. Defenders of an early initiation of HAART often cite this data. They forget three important points:

First, this is not true for the two large cohorts in which only treatment-naive patients were studied (Cozzi-Lepri 2001, Phillips 2001). These confirm our observations that even a treatment-naive patient with a high viral load and a low CD4 cell count has good chances of sufficient and long-term suppression of viral load. Under these circumstances, the initial lab values are less important - if the patient is compliant! Even in the French APROCO Cohort, in which greater differentiation existed between treatment-naive and treatment-experienced patients (Le Moing 2002), treatment-naive patients with a high viral load at baseline showed at most an insignificant negative trend. That viral load and CD4 cell count have predictive values in all cohort studies in which most (up to 91 %) patients included were usually pre-treated with NRTIs, indicates one thing above all: virological success of HAART may be compromised in patients with prolonged mono or dual therapy. Previous nucleoside analog therapy has been a risk factor for virological treatment failure in many cohorts (Casado 1998, Deeks 1999, Chaisson 2000, Grabar 2000, Le Moing 2002). In the HOPS Cohort, lack of prior therapy was decisive particularly for long-term treatment success (Holmberg 2003). As there are fortunately now very few patients on mono or dual therapy who have to change to HAART, it is justified to concentrate exclusively on treatment-naive patients.

Secondly, the relative risk of virological failure was often only increased in patients with substantial immunosuppression (below 50-100 CD4 cells/^l) or very high viral load (above 100,000 copies/ml). At levels above 200 CD4 cells/^l or a viral load of less than 100,000 copies/ml, differences could generally not be detected (see below).

Thirdly, hardly any of these studies considered compliance. A patient who starts HAART under emergency conditions at 30 CD4 cells/^l (and who presumably went to the physician only shortly before or even after clinical manifestation of AIDS) may have a different view on sickness and health and may be less compliant than someone who seeks medical advice with a good CD4 count and begins HAART after thorough reflection. It seems clear that the benefit of HAART will be different for such patients. Adherence was an important and even decisive predictor in the few studies in which it has been investigated (Le Moing 2002, Wood 2003+2004).

If these aspects are considered, the issue of whether virological response is really poorer with less favorable baseline values becomes less clear cut. Even a patient with high viral load and a very low CD4 cell count can potentially control infection quite successfully! The prerequisite for this is that the drugs are taken regularly -and the regimen administered must be a potent one: data from prospective studies such as SOLO or M98-863, in which nelfinavir (a relatively weak PI) was tested against lopinavir or fosamprenavir showed poorer responses in highly viremic patients on nelfinavir.

Is immunological response less durable with a low CD4 cell count and a high viral load?

Multiple factors influence the increase in CD4 cells: duration of immunosuppres-sion, age, thymus size or extent of thymus degeneration (see chapter "Goals and Principles of Therapy"). Do these include baseline values at initiation of therapy? Astonishingly, several cohorts found no association. (Yamashita 2001, Pezzotto 2001, Cozzi-Lepri 2001). However, these studies all showed that the rise in CD4 cells is similar, although levels remained lower if the CD4 count was initially low. In addition, it is our experience that immune reconstitution is rarely complete if values were initially low; the more damaged the immune system, the less likely a complete recovery in the long run (Garcia 2004). In the Swiss Cohort, having a low CD4 cell count at baseline was a clear risk factor for not attaining 500 CD4 cells/^l after four years (Kaufmann 2002). There is also concern over the 10-15 % of patients with a discordant response where HAART is virologically extremely successful, but CD4 cell count remains low (Piketty 1998, Renaud 1999).

Another consequence of starting therapy later can be that antigen-specific immune reconstitution remains impaired, both against HIV and other pathogens. Numerous studies suggest that qualitative immune reconstitution does not initially occur at the same pace as quantitative reconstitution (Gochorov 1998, Tortatjada 2000, Leder-man 2001, Lange 2002). One can make the analogy with a patch of desert where weeds will grow before flowers. So, what are the clinical consequences of these lab data? Why does the risk of AIDS decrease so impressively and rapidly with a rising CD4 cell count? Why can even severely immunodeficient patients discontinue their anti-infectious prophylaxis quite safely, once their CD4 cell count has risen to above 200/^l? These clinical observations - at least in the short term - seem to contradict our knowledge of the currently observed immune reconstitution.

Does the risk of clinical progression remain high even after starting HAART with a low CD4 cell count and a high viral load?

Almost all studies demonstrate a clear correlation between CD4 cell count at initiation of HAART and rates of both AIDS and death (Hogg 2000, Grabar 2000, Cozzi-Lepri 2001, Kaplan 2001, Phillips 2001, Egger 2002, Kaplan 2003, Palella 2003, Sterling 2003). Patients with a CD4 count below 50/^l when starting therapy continue to have a particularly high risk for developing AIDS (Hogg 2003). In other cohorts, the risk remained elevated even below a CD4 count of 200 cells/^l (Phillips 2001, Sterling 2001, Kaplan 2003). An Italian cohort showed that increased risk of clinical progression was associated with a CD4 count that did not rise and remained below 50 CD4 cells/^l despite HAART (Cozzi-Lepri 2001).

The largest study to date on this topic was published in 2002 by the ART Cohort Collaboration. Here, several cohorts were pooled and almost 13,000 patients on HAART were analyzed. The data seems clear-cut (Egger 2002). Baseline CD4 cell count correlated highly with the probability of AIDS or death (see Table 5.4).

Table 5.4: Risk of progression in the ART Cohort Collaboration (Egger 2002)

Baseline CD4 cells/|jl

Relative risk

50-99 versus < 50

0.74 (0.62-0.89)

100-199 versus < 50

0.52 (0.44-0.63)

200-349 versus < 50

0.24 (0.20-0.30)

> 350 versus < 50

0.18 (0.14-0.22)

One should note the moderate difference between the groups above 200 CD4 cells/^l. Viral load at baseline was only relevant if it was at a very high level, i.e. above 100,000 copies/^l.

All cohorts showed very low rates of morbidity and mortality. However, the follow-up periods were usually short and lasted less than three years. More significant differences may emerge in the long term.

Above 200 CD4 cells/^l the situation becomes more complicated. Most studies have not yet been able to provide evidence for the benefit of starting therapy early (above 350 CD4 cells/^l). Table 5.5 summarizes studies on this topic.

Table 5.5: Studies on the influence of baseline CD4 count on treatment success in patients with > 350 CD4 cells/Ml and in patients with 200-350 CD4 cells/|jl at initiation of HAART.

Less AIDS, fewer deaths?

More pronounced increase in CD4 cells?

Improved vi-rological response?

Canadian Cohort (Chaisson 2000, n=553)

NA

NA

No (trend)

Italian Cohort

(Cozzi-Lepri 2001, n=1.421)

No

No

No

CDC database, USA (Kaplan 2001, n=10.885)

No

NA

NA

Baltimore Cohort (Sterling 2003, n=333)

No

NA

No

Swiss, Frankfurt, EuroSIDA Cohorts (Phillips 2001, n=3226)

No

NA

No

Swiss Cohort (matched pair analysis subgroup) (Opravil 2002, n=2x283)

Yes

NA

NA

HOPS Cohort (Palella 2003, n=1464)

Yes

NA

Yes

Barcelona Cohort, single-center (Garcia 2004, n = 861)

No

No (trend)

NA = not available

In a meta-analysis of the three large European cohorts cited above, the difference was minimal (Egger 2002). The AIDS rate was 2.3 versus 1.8, the mortality rate 1.0 versus 0.7 per 100 patient years. This means one more case of AIDS in 200 patient years! Vast randomized studies would probably be necessary to detect a difference between the two patient groups.

Another major problem is that cohort studies do not consider the success of HAART on the individual level. This problem was recently addressed: in a complex analysis, in which data from almost 10,000 treatment-naive patients from different cohorts was combined, CD4 cell counts and viral load after six months were considered in addition to the baseline values (Chene 2003). Result: the success of HAART is key for the further risk of suffering AIDS and/or dying. Baseline values were irrelevant. In other words - if HAART is successful, the initial status does not matter.

All in all, the available results, despite their limitations, do support the current trend of deferring initiation of therapy at levels above 200 CD4 cells/^l. This risk assessment will change again as soon as better combinations with better long-term tolerability become available. Some experts feel this is already the case and are proponents of starting earlier (Holmberg 2004, Schechter 2004). However, better treatment options could also mean that it would actually be possible to start later. The evaluation of the indication for treatment must therefore continually be reexamined in the light of new developments.

Practical tips for starting therapy in asymptomatic patients

■ Below 200 CD4 cells/^l treatment should be started as soon as possible. However, even here, one should take the time to get acquainted with the patient, give proper counseling on OI prophylaxis and diagnostic procedures - it's not usually a question of having to start within a few days!

■ Above 200 CD4 cells/^l, there is more time - the individual history of the patient and course of CD4 cell count over time has to be taken into account.

■ A decrease of more than 80-100 CD4 cells/^l per year is too much! Don't delay too long in such patients!

■ There is considerable variability in laboratory values. Therefore, a single CD4 count (especially when in the range of 200-350/^l) should always be repeated before starting treatment.

■ Above 350 CD4 cells/^l: wait! Continue to monitor at least every three months.

■ The higher the viral load, the more frequent checks of CD4 count are necessary: at a viral load > 100,000 copies/ml, testing should be performed at least every two months.

■ Initiation of treatment may be justified at levels above 350 CD4 cells/^l - if viral load is very high, CD4 count is decreasing rapidly or the patient requests it (after careful counseling).

■ Check ahead of time whether a patient may be suitable for enrolment in a clinical trial.

Arguments for and against an EARLY start

• "The lower the CD4 cell count, the longer the patient will remain at risk later."

('Counter: This statement applies mainly to patients with substantial immunosuppression in whom initiation of therapy should not be debated. The earlier one starts, the more long-term toxicities will occur!)

• "A lower CD4 count often implies that only moderate immunological-virological treatment success is possible - at some stage, the destruction of the immune system is irreversible."

(Counter: This is mainly true for patients with substantial immunosuppression. However, the virological response does not seem to be reduced in treatment-naive patients.)

• "The longer one waits, the fitter the virus becomes via generation of quasi-species and immune escape variants, and the more difficult it is to treat."

(Counter: Interesting laboratory hypothesis. But, where's the relevant clinical data?)

• "The worse the condition of the patient, the worse the tolerability of HAART."

('Counter: Ancient, proven medical wisdom. But, does it apply here, where we are referring to asymptomatic patients?)

• "HIV should be treated as early as possible, as should any other infectious disease."

(Counter: HIV is not akin to any other infectious disease. HIV cannot be cured like many bacterial infections. Herpes viruses, for which there is no cure, are also treated only as needed.)

• "It has been proven that patients are less infectious on treatment." (Counter: And may be more prone to risk behavior. In addition, the risk of transmission of primary resistance mutations increases.)

Arguments for and against a LATE start

• "The earlier one starts, the sooner and more certain the side effects." (Counter: This may be true. The question is: does one more year without therapy, but with an increasing risk of AIDS, really make a difference?)

• "The earlier one starts, the higher the risk for resistance in the long term."

(Counter: OK, but... compliant patients, who have sufficient suppression of viral load, have good chances of not developing resistance, even over many years.)

• "Even a bad immune system can regenerate; after all, prophylaxis can be safely stopped after a rise in CD4 count."

(Counter: This may be true for some patients, but not for all. There are indications that the qualitative response remains impaired.)

• "It is never too late to start therapy at 200 CD4 cells."

(Counter: Who can be so sure? Some AIDS defining diseases may rarely occur even in this scenario; there is no certainty that PML or lymphoma might not develop -and if should they, good advice is hard to find.)

References on starting therapy

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2. Casado JL, Perez-Elias MJ, Antela A, et al. Predictors of long-term respones to protease inhibitor therapy in a cohort of HIV-infected patients. AIDS 1998; 12:F131-F135. http://amedeo.com/lit.php?id=9708403

3. Chaisson RE, Keruly JC, Moore RD. Association of initial CD4 cell count and viral load with response to HAART. JAMA 2000; 284:3128-29. Originalarbeit: http://hiv.net/link.php?id=204

4. Chene G, Sterne JA, May M, et al. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet 2003; 362: 679686. http://hiv.net/link.php?id=12957089

5. Cozzi-Lepri A, Phillips AN, d'Arminio Monforte A, et al. When to start HAART in chronically HIV-infected patients: evidence from the ICONA study. AIDS 2001; 15:983-90. http://amedeo.com/lit.php?id=11399980

6. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS 1999, 13:F35-43. http://amedeo.com/lit.php?id=10397555

7. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting HAART: a collaborative analysis of prospective studies. Lancet 2002; 360:119-29. http://amedeo.com/lit.php?id=12126821

8. Garcia F, De Lazzari E, Plana M, et al. Long-Term CD4+ T-Cell Response to Highly Active Antiretroviral Therapy According to Baseline CD4+ T-Cell Count. J AIDS 2004, 36:702-713. http://amedeo.com/lit.php?id=15167289

9. Gorochov G, Neumann AU, Kereveur A, et al. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 1998; 4: 215-21. http://amedeo.com/lit.php?id=9461196

10. Grabar S, Kousignian I, Sobel A, et al. Immunologic and clinical responses to highly active antiretrovi-ral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004, 18:2029-2038. http://hiv.net/link.php?id=15577624

11. Grabar S, Pradier C, Le Corfec E, et al. Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor. AIDS 2000, 14:141-9. http://amedeo.com/lit.php?id=10708284

12. Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary. Lancet 2000, 355:2147-52. http://amedeo.com/lit.php?id=10902643

13. 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. JAMA 2001; 286:2568-77. http://amedeo.com/lit.php?id=11722271

14. Holmberg SD, Hamburger ME, Moorman AC, Wood KC, Palella FJ Jr. Factors associated with maintenance of long-term plasma HIV virus RNA suppression. Clin Infect Dis 2003; 37: 702-7. http://amedeo.com/lit.php?id=12942404

15. Holmberg SD, Palella FJ Jr, Lichtenstein KA, Havlir DV. The case for earlier treatment of HIV infection. Clin Infect Dis 2004, 39:1699-704. http://amedeo.com/lit.php?id=15578373

16. Kaplan JE, Hanson DL, Cohn DL, et al. When to begin HAART? Evidence supporting initiation of therapy at CD4+ lymphocyte counts <350 cells/uL. Clin Infect Dis 2003; 37:951-8. http://hiv.net/link.php?id=13130408

17. Kaplan JE, Hanson DL, Jones JL, Dworkin MS. Viral load as an independent risk factor for opportunistic infections in HIV-infected adults and adolescents. AIDS 2001; 15:1831-6. http://amedeo.com/lit.php?id=11579245

18. Kaufmann G, Perrin L, Pantaleo G. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: The Swiss HIV Cohort Study. Abstract LB4, 9th CROI 2002, Seattle, USA. http://www.retroconference.org//2002/Abstract/14064.htm

19. Lane HC, Neaton JD. When to start therapy for HIV infection: a swinging pendulum in search of data. Ann Intern Med 2003;138:680-1.

20. Lange CG, Valdez H, Medvik K, Asaad R, Lederman MM. CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on phenotypic and functional immune restoration in HIV-1 infection. Clin Immunol 2002, 102:154-61. http://amedeo.com/lit.php?id=11846457

21. Le Moing V, Chene G, Carrieri MP, et al. Predictors of virological rebound in HIV-1-infected patients initiating a protease inhibitor-containing regimen. AIDS 2002, 16:21-9. http://amedeo.com/lit.php?id=11741159

22. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999, 353:863-8. http://amedeo.com/lit.php?id=10093977

23. Lederman MM, McKinnis R, Kelleher D, et al. Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase. AIDS 2000, 14: 2635-42. http://amedeo.com/lit.php?id=11125881

24. Lederman MM. Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 2001, Suppl 2:S11-5. http://amedeo.com/lit.php?id=11424971

Lyles RH, Munoz A, Yamashita TE, et al. Natural history of HIV type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. J Infect Dis 2000, 181:872-880. http://amedeo.com/lit.php?id=10720507

Mellors JW, Munoz AM, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997, 126:946-954. http://amedeo.com/lit.php?id=9182471

Miller V, Staszewski S, Sabin C, et al. CD4 lymphocyte count as a predictor of the duration of HAART-induced suppression of HIV load. J Infect Dis 1999, 180:530-3. http://amedeo.com/lit.php?id=10395876

Mocroft A, Devereux H, Kinloch-de-Loes S, et al. Immunological, virological and clinical response to highly active antiretroviral therapy treatment regimens in a complete clinic population. AIDS 2000, 14:1545-1552

Mocroft A, Gill MJ, Davidson W, Phillips AN. Predictors of a viral response and subsequent virological treatment failure in patients with HIV starting a protease inhibitor. AIDS 1998, 12:2161-2167.

Mocroft A, Phillips AN, Lundgren JD. HIV survival benefit associated with earlier antiviral therapy. Ann Intern Med 2004, 140:578-9. http://hiv.net/link.php?id=15068990

Opravil M, Ledergerber B, Furrer H, et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count > 350 x 10(6)/l. AIDS 2002, 16:1371-81. http://amedeo.com/lit.php?id=12131214

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6. How to Start with HAART

Christian Hoffmann, Fiona Mulcahy

Once the decision has been made that HAART is necessary, the next question is: what to start with? More than two dozen drugs are now available, and the number of possible combinations is almost infinite. Of course, it is preferable that every treatment-naive patient participates in a clinical study. This is the only way that differences between the various combinations can be established in the future, which will ultimately further improve the quality of treatment. In the past year, several combinations turned out to be suboptimal, which would never have emerged without the conduction of controlled studies. However, in practice it is not always possible to treat patients in clinical trials. For information regarding the treatment of these patients, the following summarizes the data available to date.

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