WHEN TO BEGIN THERAPY:
     Glasgow & Contrasting Retrovirus Data Presentations

Fifth International Congress on Drug Therapy in HIV Infection - October 22-26, 2000 , Glasgow, Scotland, UK
     Written for NATAP by W. David Hardy, M.D., University of California at Los Angeles

Following Dr. Hardy's Glasgow report is a report and editorial from Jules Levin, including two data-sets presented  at Retrovirus 2000 by Merck and John Bartlett. Both data-sets find that starting therapy earlier in the course of disease, when CD4s are higher and viral load is lower, leads to better outcomes. Follow-up in these studies as well as the ones presented at Glasgow are relatively short and the analyses have limitations.

The ìGlasgow Conferenceî, as it has come to be known since its inception in 1992, again lived up to its reputation in that what emerged from it was a uniquely European perspective on the treatment of HIV infection.  Unlike previous years when monumental HIV therapy studies were first presented (e.g., AZT/3TC data in 1994), no earth-shaking therapeutic advances were unveiled at this conference.  Instead, several  thought-provoking, comprehensive plenary presentations addressing the current controversial topics regarding antiretroviral therapy (ART) were delivered by notable experts.  This article will summarize the salient points made in a selection of these.  Almost all the clinical trial data presented at this conference had already been presented at other conferences this year (World AIDS Conference- Durban, ICCAC-Toronto) and thus will not be reviewed here.  In addition, results from analyses of 4 large European databases investigating virologic and immunologic outcomes of starting ART at various HIV RNA and CD4 cell levels will also be discussed.

Planning First-Line (and therefore second-line) Therapy

Scott Hammer, M.D. from Columbia University School of Medicine in New York City began by addressing the still unanswered and challenging question of when to initiate ART.He described both a CD4 cell as well as a HIV RNA equipoise that have evolved from past studies and are continuing to be refined (or at least extended) by new studies (such as two presented at this congress ñ see Phillips and Lepri-Cozzi below). He noted that past analyses from the large EuroSIDA database has demonstrated that both virologic and clinical outcome are significantly compromised if ART is started in patients with <200 CD4 cells/mL (Miller V, 1998). He then briefly mentioned the recent data from both Andrew Phillips and Allesandro Lepri-Cozzi (see details below) which agreed that there was no advantage to starting ART at a CD4 cell count >350 cells/mL compared to starting at CD4 cell counts between 200 to 350 cells/mL. These provocative, new data suggest that waiting to start ART at a point of more advanced immunodeficiency may be just as effective and safe as starting at higher CD4 cell counts.Based upon these old and new data, Hammer constructed the diagram below in regard to using CD4 cell counts as a marker for initiating ART.

He then went on to discuss using HIV RNA levels as criteria for starting ART citing data from ACTG study 320 (AZT/3TC vs AZT/3TC/indinavir in naÔve patients with CD4 cell counts <200 cells/mL, which he chaired).  He noted that the proportion of patients whose HIV RNA was <50 cps/mL at week 24 of treatment correlated directly with the level of their baseline HIV RNA:  <5000 cps/mL- 59%, 5000-50,000 cps/mL-44%, 50,000-499,000-24% and >500,000 cps/mL-14%.  Thus in a patient population already meeting CD4 cell criteria (i.e., <200 cells/mL), lower viral load at baseline further predicted improved virologic response.  As above with CD4 cells, he constructed a second diagram based upon HIV RNA considerations for initiating ART:

Even with these evidence-based criteria for initiating ART, Hammer acknowledge the ìgood but incompleteî nature of CD4 cell counts and HIVRNA levels as surrogate markers for the clinical progression of HIV infection.  He added that they can each best be thought of as a biologic continuum with specific variability present in both such as the lower  HIV RNA levels seen in ART-naÔve women compared to men which must be take into account when starting ART.   

Noting that there are now 16 licensed antiretroviral agents in the U. S., he enumerated the most important considerations for predicting good response to ART once a decision to start has been made:  potency, patient commitment to adherence, side effect profile, potential for future options, patient-specific co-morbid conditions (active injection drug use, chronic hepatitis B or C) potential for development of resistance, continuous access to medications and cost of therapy.  All of these factors are equally important and highly variable based on individual patient considerations.

When considering specific initial regimens, he gave equal weight to those made up of a single PI +/- lowñdose ritonavir (RTV) and 2 NRTIs, an NNRTI and 2 NRTIs and 3 NRTIs based upon  equivalent results of completed and on-going clinical trials comparing these options.  He also mentioned a strategic approach of initiating treatment with a dual PI and 2 NRTIs with the intention to switch to a simpler regimen such as a NNRTI and 2 NRTIs or perhaps an NNRTI and a single PI (to avoid NRTI toxicity) following effective viral load suppression.  He noted that strategies such as these may avoid the troublesome long-term adverse effects of PI and/or NRTI regimens such as lipodystrophy, lipoatrophy ,hyperlipidemias and mitochondrial toxicities as well as preserving future options.  Data on these strategies is very limited to date. 

Strategizing: planning  first & second regimens

Hammer mentioned that consideration of downstream second line options for ART are also important in selecting initial therapy.  Potential for constructing a successful second line regimen which maximally suppresses HIV RNA must be taken into account.  Resistance testing to detect which agent(s) have failed is often predictable and therefore second- and even third-line regimens can sometimes be anticipated when selecting the first one.  Most commonly this turns out to be resistance to 3TC or an NNRTI due to their high susceptibility to single mutation resistance.  Knowing this may allow clinicians to plan multiple regimens in advance.

Consider Both CD4 & Viral load in Deciding When to Begin Therapy

In closing, Hammer pointed out some still unresolved dilemmas comparing initial ART options.  Whether a PI-based, NNRTI-based or triple NRTI regimen is best may be answered by the results of on going clinical trials such as ACTG-384, Initio, and ACTG A5095 which are comparing these 3 options.  The most effective sequencing of NRTIs may also be answered by ACTG-384.  Finally, whether sequencing of PIs can be effectively accomplished and in what order has yet to be determined and clinical trials addressing this issue are currently being planned or have only just begun.  The most appropriate and effective use of dual PI/enhanced PI regimens such as lopinavir/ritonavir has also yet to be determined.  In summary, he cautioned not to wait to start ART at CD4 cell counts <200/ml noting that several studies have documented greatest safety and efficacy beginning treatment somewhere between 200 and 500 CD4 cells/ml.  HIV RNA levels must also be factored in when choosing initial therapy.  Maximal viral suppression remains the primary goal of any initial ART regimen.

Treatment Failure and Itís Management

Professor Sven Danner of the Academic Free University in Amsterdam, tackled the perplexing and multi-faceted issue of ART failure and how to best approach it.  He initially attempted to define the different ways of measuring ART failure noting virologic, immunologic, and clinical parameters must be considered.  Virologic failure appears to be best correlated with the nadir (lowest level) of HIV RNA in response to an ART regimen.  He cited data from the INCAS study which demonstrated that the proportion of patients experiencing virologic failure (HIV RNA >400 cps/ml) at 48 weeks of follow up correlated with the initial lowest viral load in response to the study regimens: <20cps/ml 20 %, 20-400 cps/ml 80 % and > 400 cps/ml 85%. While these data are historical now, they do clearly demonstrate the importance of maximal viral load suppressionís effect on the durability of ART.

What is failure?

Immunologic failure in regard to ART is not as straightforward or well studied.  Danner cited a publication by Grabar, et al (Annals of Internal Medicine) which compared virologic and immunologic response to ART.  Optimally, an ART regimen will produce both an immunologic and virologic response. However,  immunologic response  despite virologic failure is preferable to the converse situation in that a discordant CD4 cell increase despite virologic rebound occurs commonly in many patients and may last for two to three years.  Thus rising viral load (virologic failure) must be carefully interpreted in the context of a stable, rising or declining trend in CD4 cell number as far as deciding to change an ART regimen.

He also noted that intensification strategies, where one or two new agents are added to a less than suppressive ART regimen result in different virologic outcomes depending upon when this intervention is introduced.  As demonstrated by the Prometheus Study in which D4T was added to a regimen of ritonavir/saquinavir alone, produced a durable decline in HIV RNA in patients whose viral load was declining but had not reached a nadir by 18 weeks, as opposed to patients in whose viral load was rebounding following an initial nadir response.  This study teaches us the difference in management of sub-optimal response to ART versus management of rebounding HIV RNA.  The former may be successfully treated with intensification strategies whereas the latter  probably cannot.

Danner cited a telling statistic from the ATHENA (Antiretroviral Therapy Evaluation in The Netherlands) study  which has demonstrated that 50 % of patients change their initial ART by the 18^th  month of treatment.  While multiple causes for this are likely, Professor Danner cautioned that if obvious reasons for virologic or immunologic failure are not evident, a careful review with the patient concerning his/hers adherence to the regimen must be undertaken.  This point yet again boldly underscores the necessity of clear communication between patient and health care provider to ensure that proper adherence to an ART regimen is truly occurring.  This issue continues to prevail across all evaluations of treatment success or failure transcending all other reasons.

Once adherence is assured, Danner recommended several potential strategies for managing ART failure including:  1) pharmacologic boosting of a primary PI with low-dose ritonavir (notably indinavir/ritonavir and 2 new NRTIs as salvage therapy), 2) use of a new drug combination with an elevated IC90 for treatment of resistant HIV (e.g., lopinavir/ritonavir), 3) use of a drug from an existing class of ART with a new and potentially more effective resistance profile (e.g., tipranavir +/- ritonavir) and 4) use of drugs from a new class, of ART (e.g., T ñ20, other inhibitors).  Further, he recommended the use of drug level testing (once adherence is reliably confirmed) to ensure that the minimal drug concentrations are being achieved and are suppressive for the specific virus being treated.  He cautioned that if a discordant HIV RNA/CD4 cell relationship is present (stable or rising CD4 cell count with rising HIV RNA), then a ìwait and see: approach may be taken until the CD4 cell count begins to decline.  Once this occurs however, one or more of the 4 intervention strategies outlined above must be implemented. 

Treatment Interruptions

Bernard Hirschel from Geneva, Switzerland described 3 types of strategic treatment interruptions (STIs) including the following:

1) STI during primary HIV infection (PHI) whose theoretic goal is to decrease viremia and establish a vigorous immune response against HIV by stopping destruction of CD4 cells allowing them to direct a cytotoxic T- lymphocyte (CTL) response,

2) STI during chronic HIV infection (CHI) with elevated viral load due to a highly resistant virus quasispecies; the goals here are to decrease cost and toxicity associated with ART and to remove the selective pressure caused by the ART and theoretically allow the virus to revert to a more easily treatable wildtype species,

3) STI during CHI with undectable HIV RNA; the goals here are to also decrease cost and toxicity associated with ART as well as to attempt to restore an anti-HIV immune response.

In regard to the first type of STI during PHI, Herschel cited the recent publication by Rosenberg et al, noting preliminarily promising results among 5 patients treated with ART during acute HIV infection which seemed to demonstrate some early evidence of preserved CTL activity against HIV following interruption of treatment.  Caveats for practical application of this strategy include the rare opportunity to intervene during PHI and the lack of long term results associated with treatment during acute infection.

(Comments from Jules Levin: one additional caveat is that cause & effect has not clearly been established between preserved CTL activity and suppressed HIV without therapy in the Walker-Rosenberg studies in acute infection).

STI during CHI as a strategy to manage resistance to ART has been studied by at least two groups (Frankfurt Cohort Study-Miller et al, Swiss Cohort Study, Sabin et al). While decreases in HIV RNA of 1.0 to 2.0 log 10 have been noted, remarkable decreases in CD4 cell counts of 80 to 114 cells/ml have also occurred.  Whether this strategy will ever be a practical approach to managing resistance to ART remains to be seen and should not be undertaken casually due to the marked loss of CD4 cells in these pilot trials.  A comparative randomized trial of STI for this purpose is currently under design by Katlama and Youle stemming from the recent STI conference in Chicago  in October. 

(Comments: In addition to decreased CD4s, Miller has also reported in her retrospective analysis of patient records increased viral load and a number of opportunistic infections. Several researchers have reported resistance is present despite an appearance of return to wild-type.  At  the Salvage Therapy Workshop in Chicago in April 2000, Miller also reported that among the original 33who experienced an initial  viral load response at least 73% experienced a viral load rebound within 78 days. Miller also reported that 74% recovered their lost CD4s but with an estimated time of 251 days. Collectively, these findings raise questions about the safety of stopping therapy in these circumstances).

NATAP's report on Miler's presentation at the Salvage Workshop can be read in the Conference Reports section of the web site, here is a direct link:

Therapy Interruptions and New Data Reported at the Salvage Therapy Workshop

Perhaps the most controversial and most provocative STI strategy, that which attempts to restore anti-HIV immune response in persons with long-term undetectable HIV RNA in response to ART, has been initially studied by the Swiss Spanish Interruption of Treatment Trial (SSITT). Herschel, chairman of the study reported on the results of 54 patients who had completed at least 52 weeks of this trial.  In order to be enrolled in this trial all patients had to have HIV RNA <50 cps/ml for at least 6 months (actual median time 22 months), had to have no previous change in HAART due to virologic failure (actual median time 26 months continuous HAART), CD4 cell count >300/ml (actual median CD4 cell count 727/ml) and were receiving there first HAART regimen.

Patients received HAART for 8 weeks followed by no therapy for 2 weeks for 4 cycles or 40 weeks and then HAART is discontinued and patients are monitored closely for changes in HIV RNA.  The primary end point of this ongoing trial is to measure the proportion of patients with HIV RNA <5000 cps/ml after the fourth cycle.  The status of the 54 patients at week 52 is as follows: 17 patients discontinued the protocol prior to week 40 for a variety of reasons:  4-voluntary withdrawal, 1-patient who developed an acute retroviral syndrome during a treatment interruption, 12-rebound viral load >5000 after first cycle.  Of the remaining 37 patients, 19 had viral loads >5000 cps/ml, 9 had viral loads <5000cps/ml and 9 are still under evaluation.  Median rebound HIV RNA at weeks 2, 12, 22, and 32 (at the conclusion of each treatment interruption) were reported to be 2.9, 2.8, 3.0, and 3.0 log 10, respectively.  Resistance to both 3TC and nelfinavir was noted in one patient at week 24.

In summary, Herschel emphasized that the preliminary and still ongoing data from the study has not demonstrated any evidence of decreasing HIV RNA with successive treatment interruptions in this seemingly optimal group of HAART-responding patients.  He cautioned that while specific immunological studies measuring CTL activity are yet to be finalized, no anti-HIV effect appears evident so far.  Complete follow up of all 80 patients enrolled in the study is still ongoing. Determination of the efficacy of this strategy must await final study analysis.  He did note that besides the one discontinuation for symptomatic acute retroviral syndrome, the strategy appears safe with little chance of development of resistance.

(Comments from Jules Levin: in follow-up discussion with Dr Hirschel on January 3, he told me as of now preliminary data shows 20% of patients who started 12 week interruption after study week 40 have <5000 copies/ml. He is looking for predictors to see if you can pre-select who might respond to stopping therapy with control of HIV. But, the serial interruptions do not appear to stimulate control of HIV. He saw HIV specific CD8 responses during interruptions but they did not correlate with viral control. At the end of 40 weeks average CD4s were 700 and declined about 100 to 600. Hirschel made several cautionary notes about the CD4 data: these are preliminary data, the 100 CD4 decline does not reflect what could happen after longer interruption [CD4 decline could increase if person is off therapy for longer time], and in particular cautioned about the CD4 decline for a person with lower CD4s when interrupting therapy. Some doctors report seeing a 30% decline in CD4 after interrupting therapy. So if a person has low CD4s to begin with, caution should be followed: Hirschel recommends close monitoring with lab work every two weeks; and consider PCP prophylaxis if CD4s decline to 200.)

Dr. Hirschel is a guest on the weekly NATAP radio show "Living Well With HIV & Hepatitis" airing
Sunday January 21 on WOR 710 AM 11pm-12 Midnight in New York City.

(More Comments: There are risks to STIs--Some patients have reportedly seen their viral loads rebound above their baseline levels after interrupting therapy; some patients have not been able to get viral load back to undetectable; we don't know for sure whether resistance is a concern although several studies show only 2-3 people developing  resistance; what is the affect over the longer term of re-seeding reservoirs (such as lymph tissues)?  We donít know; what is the long-term affect of lowering and raising CD4s & viral load back & forth: we don't know. There are mixed opinions about these concerns I raised: some researchers share these concerns and others do not.

As mentioned above , it appears that evidence is mounting that therapy interruptions will not lead to control of HIV without therapy in chronic HIV. Still 1 small Spanish study did show HIV could be controlled with repeated interruptions, continuing research is important to explore this concept and several studies are ongoing.

For example, what about stopping therapy just to take a break? An additional type of interruption is to take one just to take a break from therapy. Studies are ongoing  and planned to explore safety and risks. If such interruptions are safe, another question is--can side effects and toxicities be reduced by taking interruptions? If a person wants to experiment with therapy interruptions, they should consider do so in a clinical trial. If a person insists on doing it on their own, they should be monitored every 2 weeks for CD4s and viral load).

For a recent Summary Update on Therapy Interruptions and a report from Eric Rosenberg on his study findings, see:

Therapy Interruptions

Optimal Time to Initiate HAART Based on Baseline CD4 Cells and HIV RNA

Probably the most provocative data reported at this conference came from two related but independent statistical analyses of European databases addressing when to start HAART.  Both of these evaluated the vial load response to HAART when initiated at different CD4 cell ranges.  Interestingly, the conclusions from each of these reports were identical.  Their impact on initiation of HAART may be of great consequence should these results be confirmed by other studies.

Andrew Phillips, et Al, from the Royal Free and University College Medical School in London presented an evaluation of 272 HAART- naÔve patients initiating therapy (at least 3 anti-HIV agents) since 1986.  Three large European databases including the Swiss HIV Cohort, Frankfurt HIV Cohort and the EuroSIDA Study Group were used for this analysis.  Median follow up time after the initiation of HART was 101 weeks.  Survival analysis techniques were used to assess the relationship between baseline CD4 cell count, viral load and virologic response to HAART.  Patients were stratified to 3 baseline CD4 cell cohorts; >200, 200-349 and >350cells/ml.  Baseline HIV RNA cohorts were stratified by <10,000, 10,000-100,000 and ..>100,000cps/ml.  Virologic response was defined as HIV RNA <500 cps/ml by 32 weeks of treatment.  Virologic rebound was defined as HIV RNA >500cps/ml on 2 occasions following virologic response as defined above. 

Overall 2346 (86%) experienced viral suppression <500 cps/ml by 32 weeks.  Relative hazards (in a Cox model containing viral load, age, sex, HIV exposure category, 3/greater that or equal to 4 anti-HIV drugs, previous AIDS diagnosis, use of saquinavir  hgc, calendar year and clinic site) of achieving a virologic response were 1.07 (95% CI 0.96-1.20, not significant) and 0.88 (0.79-0.99, significant) for CD4 cell cohorts of 200-349/ml and <200/ml, respectively compared to >350/ml.  For baseline viral load, the relative hazards were 1.03 (0.90-1.18, not significant) and 0.70 (0.61-0.80, significant) for viral loads of 10,000-99,999 and >100,000cps/ml, respectively compared with <10,000 cps/ml.  Smaller baseline CD4 cell and HIV RNA stratification cohorts further supported these results. (Thus, there was more risk if VL was >100,000 or if CD4 was <200. CD4s 200-350 or >350 presented similar results).

Among those patients with a virologic response <500cps/ml, 461(20%) subsequently experienced a viral rebound >500cps/ml on at least 2 occasions.  No trend for increasing rate of virologic rebound with lower baseline CD4 cell count or higher HIV RNA after adjustment for relevant factors was seen. These authors also reported similar results for virologic response to defined as HIV RNA <50cps/ml. They also reported that changes in initial HAART regimens were similar among all 3 CD4 and HIV RNA cohorts. Although there were slightly more regimen changes among the patients initiating HAART with <200CD4 cells/ml, changes were identical between the other 2 groups. 

The authors of this report conclude that for those treatment-naÔve patients with CD4 cell counts >200/ml and HIV RNA <100,000cps/ml there is no difference in the chance of virologic response to HAART or virologic rebound following initial response across the entire cohort.  The only point at which chance of virologic response or rebound diminished was when baseline CD4 cell count fell below 200 CD4 cells or HIV RNA rose above 100,000 cps/ml.

Following on the heels of this provocative report, Cozzi-Lepri et al, presented a similar report which evaluated virologic, immunologic, and clinical response to HAART among patients initiating treatment at various CD4 cell counts.  Drawing from the I.CO. N.A. (Italian Cohort of patients NaÔve to Antiretrovirals) database, 1329 naÔve patients starting HAART were stratified according to baseline CD4 cell count (<200, 201-350 and >350cells/ml) and followed a median of 24 weeks.  Primary endpoints for this study were:  increase in CD4 cell count, time to virologic failure (as opposed to virologic response in the study above by Phillips et al) and rate of AIDS/death after initiation of HAART 

Mean increase in CD4 cell count was 296, 312 and 151 cells /ml among patients receiving HAART with <200, 201-350 and >350 CD4 cells/ml, respectively.  Patients starting HAART with a CD4 cell count <200 cells/ml had a higher risk of subsequent virologic failure (relative hazard=1.33  95% CI:  1.02-1.73, significant) compared to patients starting with a CD4 cell count >350/ml.  In contrast there was no difference in risk of virologic failure between patients starting HAART with a CD4 cell count of 201-350 and those starting with a CD4 cell count >350 (relative hazard=1.01  95%  CI:  0.74-1.39, not significant).  The rate of new AIDS-defining diseases or death in patients who started HAART with a CD4 cell count <50/ml was 0.03per person-year (95% CI:  0.00-1.32) during the time in which the patientsí CD4 cell count was raised to >200/ml. Cozzi did not perform an analysis using the <50 copy test.

The authors conclude that this nonrandomized study, while addressing only some of the multiple aspects to initiating HAART, does not show any clear immunologic or virologic benefit to starting HAART at a CD4 cell count >350 compared to starting at CD4 cell count between 200 to 350.  These data also confirm that CD4 cell counts are clinically meaningful in that they are associated with a reduced risk of AIDS and death when they increase above 200 cells/ml.

These related but independent reports by Phillips et al and Cozzi-Lepri et al, derived from 4 large European observational databases, report results which further whittle down our long-held notion that HAART is most beneficial if started when CD4 cell counts repeatedly drop below 500 cells/ml. In the UK (where both of these analyses were carried out), it is recommended that HAART not be started until the CD4 cell counts repeatedly drops below 350 cells/ml due to a lack of demonstrable benefit if started earlier.  These two studies confirm this approach and imply that waiting to start HAART is safe as long as it is initiated before the CD4 cells drop below 200cells/ml.  Is this waiting too late or are we in the United States too ìtreatment happyî preferring to start HAART earlier than we really need to do so?

Reports like these challenge our previously held, not always well-substantiated beliefs about treating HIV and cause us to thoughtfully pause and reflect on our treatment practices.  How willing are we to factor data like these into our treatment algorithms??  Do we believe and accept them as a further refinement of the ìart of HAARTî or do we reject them because they are ìEuropeanî and conflict with what we have always held as true ñ the earlier we treat, the better our patients will do.  Do we yet clearly appreciate the potency and confirmed benefits of HAART as well as its short and long-term adverse side effects to know best when to use this resource to treat a life-long, chronic disease??    While no answers to these questions are immediately evident, it is clear that we must be willing to hear these data with an open and willing mind and allow ourselves not to hang onto old ideas just because the make us feel comfortable and secure  in a field that has an ongoing reputation for being ever-changing and always intellectually as well as personally challenging.

When To Begin Therapy
     Retrovirus & Glasgow studies: Initial Response To Therapy Based on CD4 & Viral Load Likelihood of Virologic Failure (500 copies/ml)
     Written by Jules Levin

In Glasgow, Phillips and Cozzi reported retrospective analyses (2 year follow-up) of several large  databases  in Europe for patients receiving HAART. They are reviewed below by David Hardy for NATAP. Their findings report that a person is equally likely to reach undetectable viral load (initial response to therapy) whether they started when their CD4 count was 200-350 or >350. Phillips' findings report that if a person's viral load was <100,000 the ability to reach <500 copies/ml was not compromised. But if viral load was >100,000 viral response was compromised. Their data reported that the probability of virologic failure was the same whether a person started therapy with 200-350 CD4s or >350 CD4s. Their studies showed CD4 response in terms of the number of CD4 increase was similar whether starting therapy at 200-350 or >350. Both Cozzi & Phillips datasets showed that starting therapy when CD4s are below 200 is less effective:  a patient is less likely to reach <500 copies/ml and  there is a higher likelihood of virologic failure.

At best, this data shows CD4 & virologic response should be equal whether you start therapy at 200-350 or >350 CD4s. It does not address the question: what about the affect on the immune system long-term after letting CD4s decline to 200-350; will there be more cancers? Is there irretrievable immune damage? The European data does not, in my opinion, tell us when is the best time to start therapy but suggests when it is not ok to begin therapy. In other words, waiting til CD4s are below 200 or viral load is >100,000 appears to be risky.

Retrovirus Conference 2000:
     Starting Therapy Earlier Appears More Beneficial

At the February 2000 Retrovirus Conference, Merck presented a retrospective analysis of 4 studies (all IDV+2 nukes) looking at starting therapy at 4 different disease stages: acute infection, and early, intermediate or late disease. The data shows that individuals starting therapy in acute infection or in early disease (CD4s >500) were more likely to reach <50 copies/ml. In the 2 early treatment protocols (042, 060) median baseline CD4s were >500 and viral loads were 91,000 (042) and 7700 (060), and 83% and 80% had <50 copies/ml, respectively. Follow-up was 48 weeks. For protocols 035 (intermediate disease) and 039 (advanced disease), median CD4s were 133 and 15, respectively; median baseline viral loads were 41,900 and 76,900, respectively. In follow-up, 67% and 47% had <50 copies/ml. CD4 increases were 212 (042), 164 (060), 187 (035) and 126 (039). The trend was similar for achieving <500 copies/ml.

John Bartlett from Johns Hopkins showed follow-up data at 60 weeks from a retrospective analysis of 680 patients on HAART, and showed that patients were more likely to reach <400 copies/ml and to maintain it when starting therapy at >350 CD4s compared to 200-350 CD4s. When starting therapy after CD4s were 200 or less, virologic response was less. He concluded that he supported "early use" of HAART.

By multivariate logistic regression, starting HAART with a CD4 > 350 cells/mm^{3} was associated with a relative odds (RO) of undetectable VL of 1.90 (95% CI: 1.22, 2.70; p=0.003) and starting at 200-350 cells/mm^{3} with a RO = 1.32 (95% CI: .83, 2.1; p=0.23) compared to CD4 < 200 cells/mm' controlling for baseline VL > 100,000 copies/ml (RO=0.69, p=0.04), injecting drug use (RO=0.68, p=0.04) and, in a subset of patients who had adherence interview, missing > 3 doses of HAART in the past 2 weeks (RO=0.53, p=0.02).

Patients are less likely to achieve a durable undetectable VL if HAART is first started when the CD4 is < 350 cells/mm^{3} than if it is > 350 cells/mm^{3}, supporting the use of "early" HAART.

EDITORIAL:
     So, When Should Therapy Be Started?

An often heard phrase is--a person should begin when they are ready to make the commitment. It is important that a person be prepared for the challenges in being adherent and for the potential side effects & toxicities that may occur. No one likes the side effects & toxicities experienced after starting HAART. However, I think the data is convincing enough in saying that earlier treatment is more effective in achieving and maintaining better virologic & immunologic response. The decision of when to begin therapy is a personal one between doctor & well informed patients. A well informed decision should balance the benefits & shortcomings or starting therapy early or later. In deferring therapy, a person will defer experiencing side effects & toxicities and will not have to be adherent. So, current quality of life is better. However, the person may be less likely to achieve <50 copies/ml and to maintain it durably. The ability to increase CD4 to a relatively good level may be impaired. Of course, in starting therapy, the viral & immune response  may be better but side effects & toxicities may occur.

     CD4s Are Better On The Way Down Than On The Way Up

One interesting point doesn't get much attention anymore in the discussions of this issue, although it used to be a mantra. Many people hold the opinion that CD4s are more effective & functional before they decline than after they go back up after HAART. A person's original 500 CD4s appear more effective & functional than the 500 one achieves after HAART following a decline to say 200. That said, if a person defers therapy til CD4s are 300, have they let their immune system decline too much? Have they lost immune system response to certain cancers or diseases they would have had if they started therapy when CD4s were 400 or 500. For example, is a lymphoma more likely to occur if CD4s are permitted to decline to 300 before starting therapy? We already know that in general people are able to restore protective immunity against common opportunistic infections after regaining lost CD4s following HAART.

DURBAN:
     Starting at >350 CD4s may be safer

Finally, at Durban interesting studies on when to begin therapy were presented. In a study with limitations (observational, retrospective, non-randomized) John Kaplan from the CDC found starting therapy when CD4s were >350 is safer than when CD4s are <350. Kaplan analyzed data from the CDC Adult & Adolescent Spectrum of HIV Disease Project (ASD), a medical review study of HIV-infected persons in 11 US cities. Included in this report is a discussion of Tim Sterling's study on viral load differences between men & women. Several studies have found differences in early disease which appear to even out further in the disease course. But the burning question remains--are there real differences in disease pathogenesis, outcome, and response to therapy between men and women.

See also:
     Report 33 - WHEN TO BEGIN THERAPY?