Mark Harrington writes, "As someone who's spent the last twelve years of my life trying to encourage more and better AIDS research, and has worked with community groups to help push Congress and three Presidents to provide more resources for that research, it's profoundly disappointing that the leaders of the research effort—both at NIH and in the lavishly funded ADULT ACTG and the smaller, but still substantial CPCRA—have signally failed to do anything more to address the question of 'When to start' than to reluctantly replace one set of guidelines based on expert opinion with another." His brief history of where we are and how we got there is up on the TAG web site and excerpted below.

A newly revised set of US government guidelines on when to start antiretroviral therapy, despite repudiating the "hit early, hit hard" strategy which has predominated in the USA since the Vancouver AIDS conference in 1996, merited only a peripheral presence at the 8th Annual Retrovirus Conference held in Chicago from 3-8 February 2001.

• Revised Federal Guidelines:
  A summary is presented here of the changes to the guidelines section, Considerations for Therapy.

  Table 4. Risks and Benefits of Delayed Initiation of Therapy and of Early Therapy in the Asymptomatic HIV-infected Patient. (Note: pdf format only )

Neither the chairs of the Health and Human Services guidelines panel nor the organizers of the Conference appeared especially eager to highlight the significant modifications that appeared in the February 2001 update of the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults & Adolescents.

Prior to the conference I heard a rumor that the Conference organizers had turned down a request by guidelines panel co-chairs Anthony S. Fauci of NIAID and John Bartlett of Johns Hopkins University for a press conference to announce the new guidelines. So, at the opening press session I questioned Retrovirus chair Connie Benson of the University of Colorado whether they had indeed turned down a request by Drs. Fauci and Bartlett. "Not at all," said Dr Benson, who is also a co-chair of the government's top HIV clinical research program. It turns out the only request she heard had come from a NIAID press person. "Do you think I would actually turn down Dr. Fauci?" she asked. And in fact, as the conference opened, the only document NIAID had shown the conference organizers was an anemic two-page press release; the Retrovirus press person had to download a copy of the new guidelines from the internet.

Why the low-key reception? Well, just as enthusiasm for the early use of AZT was deflated by the release of the Concorde study results in 1993, so do the 2001 treatment guidelines finally depose the ailing "hit early, hit hard" strategy. But for some, old strategies die hard.

Rather than trumpeting the changes by holding a press conference before the world's leading AIDS reporters in Chicago and admitting "Whoops! We were wrong! We screwed up! Maybe treating everyone with a viral load over 5-10,000 HIV RNA copies/mL wasn't such a great idea after all," the guidelines panel co-chairs and the Retrovirus organizers all felt it was more opportune—or more expedient—to skate over the matter as casually as possible, as though the new guidelines represented a simple and relatively uncontroversial recalibration of the standard of care.

An honest mistake?
Of course, we have been covering this controversy for a long time, as these titles show. When Mark Schoofs from The Wall Street Journal called me, he said, "This is a good thing. People don't have to go on therapy as early."

"Well, yes," I said, "but it would have been much better to have a clear answer from a randomized, controlled trial by now."

"Well, Tony Fauci says that's unfeasible."

"Well, if he says so, it must be true," I replied, "but if they'd started one in 1996, we might know the answer by now."

"You sound angry."

"I am angry. Thousands of people were put on therapy too early, and some of them developed life-threatening side effects, or resistance, and they would have been fine if they had just waited."

Was not seeking evidence for such a sweeping policy just an honest mistake? A gush of euphoria that the long, dark night of AIDS was over? Well, of course those promulgating the original standard of care were sincere—but they defaulted from their obligation as scientists to prove that their expert opinion was actually correct—and, considering the emergence of long-term side effects and widespread cross-resistance, it doesn't seem that they were.

Why the change now?

The death of the eradication hypothesis?
The NIH press release distributed at the conference quoted Dr. Fauci as saying "we know that we cannot eradicate HIV infection with currently available medications." But we have known that HAART cannot eradicate HIV ever since the discovery at the laboratories of Bob Siliciano, Doug Richman, and Tony Fauci in 1997 of latent HIV reservoirs in resting, provirally-integrated CD4 cells. The original HHS guidelines came out that same year, so the "hit early" approach could not have been based solely or even mainly on the feasibility of eradication.

Treat HIV like any other infectious disease?
In the minds of some, the "hit early" approach was based on the idea that, in Bruce Walker's words, we should "treat HIV-1 like any other infection—treat it." Well, yes. The question is, when? HIV-1 is not like other infections. Some, such as bacterial infections, can be cured with antibiotics. Obviously, if HIV could be cured, we would try to cure people. Persistent viral infections, such as herpes, cannot be cured, and we do not treat them chronically; instead, we only treat them when outbreaks occur. HIV is like neither bacterial infections nor herpes. It cannot be cured, it is chronic and persistent, and it never goes into full latency (unlike herpes). Treatment requires complex, expensive, sometimes toxic, combination therapy. Full adherence is difficult if not impossible, and the development of drug resistance is a constant threat.

Solid results from evidence-based medicine?
In the NIH press release, Fauci went on to say that the revised guidelines present "evidence-based recommendations for initiating antiretroviral therapy that take into account both the benefits and potential risks..." However, the guidelines themselves admit that, "The optimal time to initiate antiretroviral therapy is not known."

The "evidence" to which Dr. Fauci referred is a random grab-bag of observational studies which are contradictory and hardly definitive. One can conclude whatever one wants to from these observational studies—if you favor early treatment, you can find studies that do too, and if you favor later therapy, other studies will back you up.

Weaker evidence from observational studies?
Observational studies, despite their limitations, are practically the only "evidence" we have right now about the clinical benefits of various starting thresholds. Several large cohort studies presented at the Retrovirus conference in February 2001—most of them in poster form because they did not fit the preferred weltanschauung of the conference organizers—suggest that, while starting when the CD4 count is below 200 is clearly less effective than starting when it's above, there is no difference among groups starting with higher CD4 cut-offs; even very high viral load may make little difference.

What next?
It would be nice if we could really have treatment guidelines based on evidence from well-controlled studies. But perhaps we missed the chance to initiate such studies because so many were captivated by the euphoria that accompanied the adoption of HAART after 1996. Sometime in 1997, when David Barr and I were in Anthony Fauci's famous corner office at NIAID, we asked him to support a major clinical trial of when to start. "It's the most important question in HIV therapy," he agreed. But nothing happened. During the 1998 adult AIDS clinical trials recompetition, NIAID once again missed the opportunity to encourage—or force—the research community to address the question.

In early 2000, after considerable activist pressure, the NIAID Division of AIDS appeared to recommend $42 million in funding for a when to start trial, and held several workshops to discuss methodology and feasibility issues. These initiatives were smothered in the cradle by THE ADULT ACTG leadership and community representatives in their thrall who dismissed the feasibility of long-term research. This round of when-to-start ideas was finally buried at the NIAID Council meeting in January 2001.

As the press started to get hold of the new treatment guidelines, it was natural to ask Dr. Fauci why there were no clinical trials to answer what appeared to be such an important question. Even though the NIAID-sponsored feasibility studies had yet to be completed, Fauci told ABC News, in a story aired on January 31, 2001, that such a study would be "logistically impossible to do ... No one has yet been able to come up with a protocol."

Some have suggested doing a when-to-start study in a developing country. But in places that can barely afford HAART or the necessary infrastructure, treating people with CD4 counts over 350—or even over 200 cells/mm³—may be a luxury such countries can ill-afford, even if some so-far-undetected benefit actually accrues to such a strategy.

At the Retrovirus conference, one of the leading figures in the Adult ACTG told me that, having dismissed the idea of a randomized when-to-start study with clinical endpoints, the ADULT ACTG is now exploring the feasibility of 1) smaller randomized when-to-start studies looking at viral load, CD4 counts, and other laboratory parameters, and 2) establishing a larger observational cohort which, supposedly, could shed light on the question.

There are several problems with this approach. The smaller randomized study with surrogate markers simply wouldn't answer the question of whether people who start treatment earlier live longer or not. Obviously CD4 counts would be higher, and RNA levels lower, in the group that was treated earlier. But, this might not affect longer-term outcomes. The prospective observational study would be expensive, wouldn't answer the question any sooner than a randomized controlled trial, and would suffer from all the limitations of the observational studies described above.

It appears unlikely that any of the NIH-funded trials networks will do a controlled clinical endpoint study looking at when-to-start. It appears even less likely that such a study could be carried out in resource-poor developing country settings. Perhaps the Europeans, in conjunction with other developed countries such as Canada or Australia, may do such a study—but clinicians in those countries already tend to start treatment later.

More likely, we'll have to continue to rely on observational studies with accumulating inferences, hints and clues from smaller randomized studies, as well as new and emerging insights about predictors and correlates of various drug-related adverse events, to guide the standard of care for the next few years. ¤

"While many people with HIV are living longer, more productive lives," Michael Marco explains," a good many co-infected with the hepatitis C virus are winding up in the hospital and dying of end-stage liver disease (ESLD). As an activist who eschews hepatitis C media hype (e.g.., New York magazine's outrageous 2000 cover story, "Hepatitis C, The Silent Killer") and alarmist coinfection data from misleading, outdated and small retrospective case studies, I am here to say that we have a big problem on our hands."

End stage liver disease (ESLD) (characterized as conditions, including encephalopathy, ascites, jaundice, gastrointestinal bleeding, hepatorenal syndrome or peritonitis) in PWAs with HCV appears to be a leading cause of hospital admissions and death according to a number of U.S. and European data presentations at the 8th Conference on Retroviruses and Opportunistic Infections. Conflicting data from the conference (and recent journal articles) have also reinvigorated the old debate of whether HCV infection independently leads to accelerated disease progression and death in PWAs.

End stage liver disease as the leading cause of death in HIV clinical cohorts
Epidemiology studies from various HIV cohorts in the U.S. report coinfection in 25-75% of patients. The higher incidence rates are often found in major metropolitan inner-city clinics treating patients with a history of intravenous drug use. Many HIV clinics in southern Europe have a coinfection rate >50%. Co-infected HAART-treated individuals who are living longer and entering their late 40s and 50s are having their HCV disease go from asymptomatic to symptomatic and worse yet, from symptomatic to ESLD. For 20% of HCV-infected individuals—especially those co-infected with a nadir CD4 cell count of <200 cells/mm³—progression to ESLD is only a matter of time.

Researchers in Madrid documented a steep rise in the number of hospital admissions and deaths caused by HCV and HBV-related ESLD between 1995 and 2000. Of the 843 HIV-positive individuals seen at the institution over the five year period, 46% had viral hepatitis; about 30% of whom had HCV. Hospitalization due to ESLD rose from 5.2% in 1996 to 8.4% in 2000. In fact, 43% of all deaths among the HIV-positive individuals were caused by ESLD.

HCV ESLD was again the leading cause of death in a French HIV cohort. French researchers reported that there were 105 death recorded between 1998-1999 in their 2,200 patient cohort. HCV ESLD was the cause of 29% of the deaths. Investigators from northern Italy found that HCV ESLD was the leading cause of death in their HIV-positive individuals in 1998 and 1999. While individuals in the cohort have been followed since 1987, Dr. Di Perri noted, "ESLD associated with chronic HCV infection, which had only a minor impact on mortality until 1997, became the leading cause of death in the last two years of study."

This surge in deaths due to ESLD in co-infected individuals is not confined to southern Europe. At Cook County Hospital in Chicago where over 50% of the HIV-positive individuals have HCV, researchers there found ESLD to be the cause of death in 35% of the individuals between January 1998 and September 2000. ESLD was the second leading cause of death after sepsis (38%).

Does HCV infection negatively affect HIV disease? A number of studies presented at the Retrovirus meeting attempted to answer the controversial coinfection question: Does HCV have a negative impact on HIV disease progression and survival? The best data came from the well-established European HIV cohorts and the Johns Hopkins group.

Studies concluding, "Yes."
At the Retrovirus meeting, researchers from Montreal's McGill University presented results from a 182 HIV-positive patient retrospective chart review that revealed HCV coinfection was associated with faster progression to death and increased hospitalization. 78 HIV/HCV co-infected individuals who were compared with 104 HIV-mono-infected individuals seen at the McGill's clinic between January 1996 and June 1999. While both groups had similar baseline demographic characteristics (38 years old; 70% male; 310 CD4 cells/mm³; and an HIV RNA of 10,000 copies/ml), 23% of the co-infected individuals were on HAART compared to 35% of those infected with HIV alone.

The rate of opportunistic infection was 9.77 vs. 7.91 per 100 person years; rate of deaths: 6.67 vs. 2.27/100 person years; and hospitalization rates: 15.03 vs. 6.79/100 person years in co-infected and mono-infected patients, respectively. Coinfection was therefore associated with a faster progression to death. After adjusting for differences in baseline and follow-up measures of CD4 cell count, HIV viral load, duration of HIV infection, and use of HAART, the relative risk of death for HCV/HIV co-infected individuals was 11.7; the relative risk of hospitalization was 2.5.

Even though HAART use was controlled for, the authors speculated that the differences in HIV clinical progression "may be explained in part by the lower use of HAART." The data here are important, but it is difficult to garner definitive conclusions from such a small, retrospective single-institution case study.

The McGill study corroborates results of a much larger from the Swiss HIV Cohort which was recently published in the Lancet. 3,111 individuals initiating HAART between June 1996 and May 1999 were prospectively followed for survival, clinical progression, HIV RNA suppression, CD4 cell recovery, and HAART change according to HCV status. Of the 3,111 HIV individuals who were followed for a median of 28 months, 1,157 (37.2%) were co-infected with HCV, 1015 (87.7%) with a history of IVDU. There were significant differences in baseline HIV characteristics of the HCV-infected and HCV-uninfected individuals: 27.7% vs. 23.5% had AIDS; 58.9% vs. 52.3% were antiretroviral treatment naive; and median CD4 cell count was 172 vs. 222 cells/mm³.

After the initiation of HAART, there was no association between HCV infection and the probability of reaching an HIV RNA <400 copies/mL. Approximately 87% of all study participants suppressed their HIV RNA <400 copies/mL. There were, however, differences between the two groups with regard to CD4 cell recovery. After one year on HAART, probability of failing to increase CD4 counts by 50 cells/mm³ was 25.1% for HCV-infected study volunteers compared to 16% for the HCV-uninfected individuals (p<0.05).

At the end of follow-up, 7.5% of the HCV-infected individuals developed an OI compared to 4.7% of the HCV-uninfected ones (p= 0.001). All-cause death was also more common in the HCV-infected ones: 8.8% vs. 4% (p<0.001). Interestingly, there were significant differences in the probability of clinical progression to AIDS and death when data were stratified by active IVDU and HCV. The estimated probability of clinical progression at 2 years was: 6.6% for HCV-/no active IVDU; 9.7% for HCV+/no active IVDU; and 15% for HCV+/active IVDU.

This study is one of the first (and largest) to detect an increase in OIs and death due to coinfection with HCV. One explanation for this could be the impaired CD4 cell recovery in HCV-infected individuals on HAART. These results will definitely need to be confirmed in another study of equal size in a different country. The fact that >85% of these 3,000 Swiss individuals had an HIV RNA <400 copies/mL makes this author think that Switzerland is not "real world" when it comes to HIV and its medical management.

Impairment of CD4 cell recovery in HIV/HCV co-infected individuals on HAART was also seen in a Spanish study. Retrospective data were collected on 902 HIV-positive individuals (72% of whom were co-infected with HCV) seen between January 1998 and April 2000 to determine the immunologic and virologic impact of HCV infection on those initiating HAART. There were significant differences in baseline HIV characteristics of between the HCV-infected and HCV-uninfected individuals: mean CD4 count was 518 vs. 620 cell/mm³ and HIV RNA was 11,000 vs. 6,000 copies/mL. Similar proportions of individuals in each group were on ART (92%) and there was no difference in drug adherence (83% taking >90% of pills).

After two years, there were striking immunologic and virologic differences between the two groups. HIV RNA on average declined only 606 copies/mL (5%) in the HCV-infected group compared to 5,788 copies/mL (53%) in the HCV-uninfected group. Likewise, CD4 counts on average increased 53 cells/mm³ (11%) compared to 111 cells/mm³ (22%) in the HCV-infected and HCV-uninfected group, respectively.

While this study does not give us actual data on HIV clinical disease progression, it is interesting to note such striking differences in the surrogate markers of HIV disease progression. The authors bring up an interesting point for HIV-treating physicians to ponder: Would treating a co-infected person's HCV (regardless of liver fibrosis state) indirectly help combat the underlying HIV disease?

Studies concluding, "No."
Data from the Johns Hopkins 1,742 person HIV cohort suggest that HCV does not affect HIV disease progression or survival. Hopkins researchers followed this cohort, 45% of whom were HCV-infected, from January 1996 to June 2000 to determine outcomes of CD4 cell decline to <200 cells/mm³, development of OIs, and death. HCV-infected individuals were older, more likely to be black (85% HCV+ vs. 65% HCV-) and had past or present IVDU (85% HCV+>14% HCV-), yet no differences were observed in baseline CD4 or HIV RNA.

At the end of follow-up, no difference in HIV clinical progression was observed in the HCV co-infected individuals. Initially, an increased risk of progression to CD4 <200 cells/mm³ and death was documented in HCV-infected individuals with baseline CD4 counts between 50 and 200/mm³, however, when HAART use and lack of HIV RNA suppression to <400 copies/mL were controlled for, HCV infection was no longer significantly associated with CD4 decline or survival. Use of HAART and lack of HIV RNA suppression remained significant in the multivariate analysis. Of interest, impairment of CD4 cell recovery on HAART was also noticed in the co-infected individuals at Hopkins. With three studies documenting this fact, TAG believes that intensified research in the immunology of HCV coinfection is warranted.

Two other studies presented at the meeting—one French, one Spanish—failed to document increased HIV clinical progression or mortality in co-infected individuals. French researchers followed 995 HIV-positive individuals (58% of whom were co-infected with HCV) for 3 years. No significant increase risk of AIDS or death was noted in the HCV-infected individuals compared to the HCV-uninfected individuals. And in a 504 patient Seville HIV cohort, deaths due to liver failure increased since 1997, yet no significant difference in survival was observed between HCV-infected and HCV-uninfected individuals.

Opening up the debate of whether HCV alters HIV clinical progression adds to the never-ending list of questions in HIV/HCV coinfection clinical and basic research. In this fledgling field we desperately need large, collaborative, multicentered natural history coinfection studies (as well as treatment trials) in the U.S. and abroad—and the financial resources to implement, follow, and carry them out properly. ¤

The ADAC committee was absent of some of its members, most notably Roy "Trip" Gulick, the acting-chair. Roger Pomerantz filled in nicely for Trip, and luckily old-time HIV experts Princy Kumar (Georgetown) and Chris Mathew's (UCSD)were present for a reality check. The advisory committee was infused with some well-respected ophthalmologists who unfortunately got "stuck-on-stupid" during the question and answer period.

Roche's Mary Jean Stempien, who is considered the mother of IV ganciclovir from the late 1980s, was back at the helm presenting the valganciclovir safety and efficacy data. Emory's Dan Martin, the consummate over-accruer and good-natured ophthalmologist, was on-hand to answer the technical ophthalmologic questions.

I had wondered why the FDA's Antiviral Drug Products Division requested a public hearing on valganciclovir, the valine-ester prodrug of IV ganciclovir. The valganciclovir data are excellent and there are years of experience treating thousands of patients with IV ganciclovir. A source close to the Division told me the hearing was needed because: 1) only one trial of 160 patients was being used for efficacy analysis; and 2) the sponsor was requesting an indication for CMV induction and maintenance therapy but only had efficacy data from the 4-week randomized valganciclovir vs. IV ganciclovir induction phase.

Roche pointed out three reasons it deserved an indication for maintenance therapy:

1. Valganciclovir provides systemic exposure (AUC) comparable to IV ganciclovir;
2. Valganciclovir's efficacy in the induction phase - the most rigorous test of a CMV drug - was similar to IV ganciclovir;
3. Valganciclovir offers exposure 10-times to that of oral ganciclovir (and it's approved for maintenance), valganciclovir should be considered at least as effective for maintenance.

Mary Jean Stempien and Dan Martin were on their toes the entire day answering questions and showing a myriad of back-up slides. Some of the pharmacology questions were interesting (i.e., "Is using AUC the best gauge for determining bio-equivalence"), but most of the others were too painful to sit through.

I wondered if some of the ophthalmologists really knew HIV clinical care and understood the entire HIV-positive patient, not just his or her eyes. One ophthalmologist did not like the rate of anemia attributed to valganciclovir during the open-label maintenance phase. He repeatedly wanted to know if Roche would consider lowering the maintenance dose. Mary Jean began answering his questions simply and calmly, but when he just wouldn't let up, she lost her polite and professional tone of voice and let him have it. I have paraphrased her comments below:

Anemia is not something new! Doctors have been using ganciclovir for years and they know full well that it causes anemia. They look for it and treat it appropriately. Epogen does just fine. And with regard to lowering the dose, no, we won't lower the dose! The most important thing is to get to the MTD for val- or IV ganciclovir. Mutations occur and people fail this drug after a period of time. Even though the time to failure is longer with valganciclovir than other CMV drugs, people still fail. Look at the study data. Patients need as much drug as they can get to prevent mutations. I was so pleased her gloves were off. I was wondering how long Mary Jean would last with such nonsense. Holding my tongue, I wanted to scream out, "Where were you all with your toxicity questions when cidofovir was being approved? You were needed then to warn people that cidofovir would blow out patient's kidneys and cause death in some on HAART."

I did get a chance to deliver TAG's policy statement regarding valganciclovir's approval. This was during the open public comment portion; I was the only "public" to comment.

Since the ADAC already had a straightforward TAG statement that recommended valganciclovir for approval, I decided to discuss the questions which were soon to be voted on. With regard to its efficacy, I said that valganciclovir was comparable to ganciclovir, and it's surprising that even one study was ever completed during the HAART era. I reminded them that after 20 years of AIDS, an effective oral CMV treatment is still not available. I also reminded them that Roche headquarters in Basel wanted to stop the development of valganciclovir because of fear that CMV had gone away and there would be no market. As for its safety, I said valganciclovir is IV ganciclovir in a pill and all good HIV doctors know how to manage ganciclovir's hematological toxicities. When it came to the question of valganciclovir's effectiveness as maintenance, I informed the ADAC that most CMV drugs were approved for induction and maintenance therapy using an immediate versus deferred trial design. Such studies only told us that the drug was better than nothing (deferring) and were stopped so early by a DSMB that no real maintenance data exist. Why was the bar being suddenly raised for valganciclovir?" I ended by asking Roche to please take oral ganciclovir off the market once valganciclovir was approved. I said the pill burden was too great to make it an option for maintenance and it is not effective as CMV prophylaxis. During ADAC's discussion of the questions, Chris Mathews, who had remained silent the entire day, spoke honestly and passionately. To paraphrase Mathews, he said, the data on this drug are fine... I've needed a drug like this for my patients for years...having an oral drug is a great advance...I'm glad it's here.

When it came time to vote on questions #1: Do the Data submitted in this NDA support the safety and efficacy of valganciclovir for induction therapy of CMV retinitis?, the ADAC voted 12 yes to 1 no. After question #2 was reworded to simply ask, "Do you feel comfortable with valganciclovir being used as CMV maintenance therapy, the ADAC vote 12 yes,0 no, and 1 abstention.

For such a home run drug, this ADAC meeting was grueling. If I was that exhausted, I wonder how Mary Jean must have felt? I guess there are no easy days in Gaithersburg. ¤