Remune has been licensed by the Immune Response Corporation to the Trinity Medical Group, a Thailand-based company, for development within Thailand. Clinical trials of Remune are ongoing in Thailand, in part conducted by a leading official in the Trinity Medical group who is also an influential figure in the Thai medical/business community. A recent decision was made by Trinity Medical Group to have Remune evaluated by the Thai FDA as a drug, not as a vaccine, a decision that is ill-founded in science but which has been perceived as providing the company with an easier route to licensure. The practices that have led to the now-pending licensure of Remune in Thailand would not be permitted in the U.S., due to procedural breaches. The problems appear to include, but may not be limited to, inattention to conflict-of-interest regulations that should apply to the conduct of clinical trials by a product's sponsor.

It now appears that Remune will be licensed as a drug for use in Thailand as front-line monotherapy (i.e., the drug will be sold to HIV-infected Thai people to be used as the only therapy they are taking against HIV), despite the lack of any evidence of clinical benefit. We deplore and condemn this situation. A product developed by an American biotechnology company should not be sold to HIV-infected people in the developing world unless it has been proven to be safe and effective in the population for which the product is to be marketed, in studies which meet U.S. ethical and regulatory standards. Studies of HIV vaccine products may need to be conducted in different populations depending on the viral strains on which they were based, and taking into account the hypothesis being studied in the particular vaccine trial). That situation does not apply to Remune in this case. Indeed, all the available scientific evidence strongly suggests that Remune has no effect on the course of HIV disease when used as monotherapy. It is morally unacceptable for an American company and its Thai subsidiary to profit in any way from the sales of an ineffective drug. The sums of money spent by Thai citizens on this product will be wasted; instead, the treatment priorities in Thailand should be the provision of highly-active antiretroviral therapy (HAART) and of treatment and prophylaxis for opportunistic infections and tuberculosis.

There is an urgent need for the countries of the Western world to bring effective HIV therapies to the nations of the developing world. These efforts will be compromised if American companies behave other than ethically in attempting to sell their products. The sale of an ineffective drug in Thailand could have serious, long-term and widespread adverse implications for the reputations of Western science and industry. We therefore demand that the Immune Response Corporation and its local affiliate cancel all their attempts to make money from sales of Remune in Thailand, unless and until they develop clear evidence from properly-performed, well-controlled clinical trials that Remune preserves health or prolongs life among HIV-infected individuals when it is used, as is now proposed, as the sole modality.

TB researchers and policy-makers from around the world gathered on 3-5 June 2002 in Washington, D.C., at the 4th World TB Congress (the 3rd was held ten years ago) to mark progress and map out the next stages of the global campaign to STOP TB, which is led by the World Health Organization (WHO). Daniel Raymond prepared this report for TAGline.

Mycobacterium tuberculosis (TB) is the leading killer of people with AIDS around the world. Immune systems weakened by HIV are more susceptible to the ravages of TB, which itself speeds up progression to AIDS. Like HIV, TB is preventable and treatable, but unlike HIV, it is also curable. An uncomplicated case of drug-susceptible pulmonary tuberculosis can usually be cured with a six month regimen consisting of four drugs taken for two months, followed by two drugs taken for four months. Because many people stop taking their medications after their TB symptoms disappear, the favored approach to TB treatment involves directly-observed therapy (DOT), which increases the cure rate and reduces the incidence of multi-drug resistant (MDR) TB.

Worldwide, infection with tuberculosis is, along with HIV and malaria, the leading infectious killer. Moreover, the HIV pandemic has caused an upsurge in worldwide TB-related disease and death, in spite of a massive scale-up over the past ten years which has led to significant advances in the treatment and prevention of tuberculosis in resource-poor settings.

The Congress marked the culmination of a decade of astonishing advances and success, while ushering in a period filled with new challenges and questions. A concerted international effort, coordinated by the WHO, has led to the wide-scale adoption of DOTS (Directly Observed Therapy, Short Course), whose key elements include:

1. Sustained national political commitment to TB control;

2. Passive case detection of active TB disease via sputum microscopy;

3. Standardized short-course (six months) chemotherapy;

4. Reliable procurement and distribution systems for quality-assured drugs; and

5. A surveillance and reporting system documenting individual patient outcomes.

The DOTS strategy—devised in the early 1990s and now adopted by 148 countries—is a global public health priority due to the fact that one third of the world's population harbors TB infection, of whom 8.4 million people develop active tuberculosis, from which nearly two million die each year. Multidrug-resistant TB cases are rising in many areas, while the HIV epidemic is fueling a resurgence of TB in many high HIV prevalence areas, particularly sub-Saharan Africa and parts of Southeast Asia and the former Soviet Union. Indeed, tuberculosis accounts for at least one third of all HIV-related mortality worldwide.

Mario Raviglione from the WHO STOP TB Program reviewed developments over the last decade that spurred a renewed global commitment to fighting TB. He noted that widespread media coverage surrounding outbreaks of MDR-TB in urban settings in the developed world in the early 1990s (including New York and San Francisco) reversed two decades of decline in global concern during which TB was largely controlled in the West while in developing countries dedicated TB funding and staff were folded into broader infectious disease programs. Raviglione cited the World Bank's 1993 World Development Report as critical in establishing the cost effectiveness, and hence feasibility, of treating TB even in resource-poor settings, using the DOTS strategy.

In 1991 the World Health Assembly set targets of 70% detection of active cases and 85% cure rate of those cases. The momentum from this revived focus on TB control led to the establishment of multi-sectoral working groups, including the Stop TB Partnership, the Global Alliance on TB Drug Development, and the Global TB Drug Facility, as well as groups focusing on MDR-TB and vaccine and diagnostics development. Over the past decade WHO successfully persuaded health and finance ministers in 148 countries to implement DOTS. Ten million cases of TB disease have been treated under DOTS, and seven million people have been cured.

In contrast to the mood of optimism in TB research—including progress towards the development of new drugs and effective vaccines—the conference sessions addressing the impact of HIV on the TB epidemic had a more somber tone. People with HIV are more susceptible to TB infection and much more likely to develop active TB. In some sub-Saharan countries, which account for 70% of the world's HIV/TB coinfection cases, 40-60% of people with active TB disease are HIV positive. Peter Godfrey-Fausett from the London School of Hygiene and Tropical Medicine noted that "no country with a severe HIV epidemic is controlling TB," including those with established, well-functioning national TB control programs.

The convergence of these two epidemics has worsened the impact of each: in countries with high HIV prevalence, people are often reluctant to seek out TB treatment as they fear being tarred with the social stigma of "TB-AIDS." In some areas TB drugs such as rifampin used to treat TB are being taken to manage opportunistic infections, increasing the risk of developing MDR-TB. Moreover, while isoniazid ("INH") therapy—used as TB prophylaxis to prevent active disease—may prevent active TB, some research suggests that it does not reduce overall mortality after two to three years of follow-up—either because of TB re-exposure and reinfection or because of other HIV related causes of mortality.

Discussing the prospects of linking antiretroviral therapy to TB treatment in Africa, Nicola Hargreaves from the Malawi National TB Control Program observed that rifampin has known interactions with some antiretroviral medications, notably protease inhibitors and nevirapine. She also described a reactivation, or immune reconstitution, syndrome experienced by some patients with latent TB infection upon initiating HAART, which may lead to serious complications. Furthermore, she cited figures indicating that almost 60% of HIV+ people who die of TB despite treatment die in the first two months of TB treatment. Given these considerations, she suggested a model for treating patients presenting with both active TB and HIV:

She acknowledged that this algorithm presumed access to CD4 testing which is generally unavailable in resource poor settings. Nevertheless, Hargreaves called for a package of TB and HIV care that explicitly included ART, noting the preliminary successes of pilot ProTEST programs in South Africa and elsewhere which using voluntary counseling and testing for HIV as an entry point into various services including TB screening, opportunistic infection prophylaxis with cotrimoxazole (Bactrim), treatment of sexually transmitted diseases (STDs) and safer sex counseling, and psychosocial support services.

Some speakers and audience members questioned whether ART would have an impact on TB control, given that many people with HIV develop active TB when their CD4 counts are still well above 200, a time when most would not be on antiretroviral therapy. Peter Godfrey-Fausett remarked when TB and HIV were treated concurrently, it would be more difficult if not impossible to identify the cause of drug-related side effects such as hepatotoxicity and neuropathy which might lead some patients to discontinue prematurely their TB regimens.

David Cohn of the Denver Department of Public Health and University of Colorado argued that initiating antiretroviral therapy during TB treatment increased the risk of side effects, adherence problems, drug interactions, and paradoxical reactions (immune reconstitution syndrome). He called for carefully designed pilot studies with an operational research component. Support for the impact of antiretroviral therapy on TB rates came from a timely article appearing in the Lancet after the World TB Congress, showing that among HIV+ patients in South Africa, HAART reduced the incidence of TB by over 80%. The effect of HAART on TB was most pronounced in people with a CD4 count below 200.

Christopher Dye from WHO presented compelling data that called into question the long-term success of current strategies utilizing vertical approaches based on DOTS. While DOTS implementation has proven successful in some areas at increasing cure rates to the 85% target, the goal of 70% case detection has proven more elusive.

According to Dye's models, even with expanding DOTS to provide full coverage across the world, case detection rates will level off at about 40% of all active TB cases. Many of the "missing" cases are presumably people seeking care outside of public health systems. Cure rates are much lower in the private health care sector, which may help account for the rise in MDR-TB in some places. Dye stated that it would be necessary to broaden case-finding to the private sector, possibly by providing incentives to private providers, or to try other means of broadening the cadre of physicians who understand the DOTS approach.

The managerial discourse dominating discussions of TB control underlies the aversion towards health sector reform approaches, which raise the specter for National TB Control Programs (NTPs) of loss of budget control, disruption of lines of communication and supervision, and net loss of TB expertise and specialized experience.

The management paradigm may also explain the almost total absence of discussion during the conference of strategies for community involvement and mobilization. Ample evidence from the field and the literature indicates that people with TB take an active role in managing their health. NTPs rely on passive case finding—typically patients presenting for care with a persistent cough—but many people with TB are clearly making choices about their health care that don't necessarily lead them to NTPs. While more research is needed on the health management strategies of people with TB, it would be a mistake to frame this phenomenon solely as a "management problem" for NTPs, rather than an opportunity to develop methods to engage communities in actively participating in TB control. ¤

Estimates of HCV prevalence among people with HIV in the United States range from 30% to 50%, with even higher rates among people infected through injection drug use. In the U.S., end stage liver disease has become a leading cause of death in people with HIV. Yet national guidelines for the management of hepatitis C infection have conspiculously lagged the current state of the art. A recent government sponsored panel seeks to rectify the situation. Once again, Daniel Raymond attended on behalf of TAG and returned with all the data and dish.

The release on June 12th of a new NIH draft consensus statement, "Management of Hepatitis C: 2002" represents an important milestone in treatment, care, and research in hepatitis C virus (HCV) infection. The consensus statement was drafted by an expert panel chaired by Dr. James Boyer following two days of presentations by researchers with a question and answer period open to the public. The NIH characterizes the consensus statement as an independent report, rather than a policy paper. When the previous consensus statement was released in 1997, alpha interferon monotherapy was the standard of care, as ribavirin had not yet been approved for use in combination therapy. The new statement endorses combination therapy in all patients with biopsy results indicating portal or bridging fibrosis and inflammation and necrosis.

The panel recommends first line therapy using ribavirin in combination with pegylated interferon, a newer formulation requiring only once-weekly dosing and providing an improved sustained virological response (undetectable HCV viral load six months after treatment) approaching 50% in mono-infected patients with genotype 1 and about 80% in patients with genotypes 2 and 3. These response rates are roughly equivalent in studies using ribavirin in combination with Peg-Intron (pegylated interferon alfa-2b, approved by the FDA) and Pegasys (pegylated interferon alfa-2a, submitted for FDA approval), although a comparison study of the two versions has not been conducted.

The 2002 statement also supports treating injection drug users, reversing the 1997 stance of withholding treatment until at least six months of abstinence from drugs. The original statement was guided more by assumption than evidence, which was scant. A letter signed by a broad group of activists, service providers, doctors and researchers supported this revision in the new statement.

Drug users have not always fared so well in the efforts of hepatitis advocates; some established groups have attempted to down play the prevalence of hepatitis C infection among IDUs—as high as to 70-90%, according to some studies—out of concern for associating the stigma of drug use with people suffering from hepatitis C infection. However, an explosion of interest and concern regarding this population in recent years among service providers has led to widespread initiatives promoting education and testing, particularly in HIV outreach and needle exchange programs.

When is the optimal time to initiate hepatitis C treatment in co-infected patients?
Estimates of HCV prevalence among people with HIV in the United States range from 30% to 50%, with even higher rates among people infected through injection drug use. In the U.S., end stage liver disease has become a leading cause of death in people with HIV.

The current state of hepatitis C knowledge—and its limitations—is reflected in the guidance on HIV/HCV co-infection
The consensus statement notes that based on available data, hepatitis C treatment appears safe and reasonably effective in people with HIV. The panel calls for more research into natural history and pathogenesis, treatment safety and outcomes, and optimal dosing and duration of therapy. However, the recommendations fail to address—or, in the current version, acknowledge—the most urgent and vexing question among co-infected people and their doctors in recent years: which should be treated first, HIV or HCV—or both, simultaneously? And when is the optimal time to initiate hepatitis C treatment in co-infected patients? Research indicates that people with a CD4 count below 200 have a significantly increased risk of progression to cirrhosis, while response rates to hepatitis C treatment improve with higher CD4 levels. A liver disease specialist looking to this document for guidance on treating a co-infected patients would not find adequate reference to the influence of CD4 counts on disease progression and treatment response rates.

Hepatitis C treatment, HIV treatment and the risks of hepatotoxicity from antiretroviral medications
Major concerns for co-infected persons and their doctors include balancing decisions about whether and when to start hepatitis C treatment with the risks of hepatotoxicity from antiretroviral medications used to treat HIV. The clinical relevance of antiretroviral hepatotoxicity to risk of hepatitis C disease progression has not been established; however, the incidence of HAART-related hepatotoxicity is significantly higher in people co-infected with hepatitis C (and/or with hepatitis B). Certain medications, including nevirapine and ritonavir, have been linked to a higher rate of hepatotoxicity, but it's not clear how that should inform decisions about treatment regimens, although frequent monitoring of ALT levels and for symptoms is clearly necessary.

Does hepatitis C infection affect immune reconstitution?
A great deal of uncertainty and guesswork still governs the thinking among both patients and clinicians in the treatment of HIV/HCV co-infection. A rapidly increasing number of studies explore a range of questions related to treatment strategies, but they often yield conflicting results, use small sample sizes, have limited follow-up, or lack randomized controls. Comparisons between studies are made difficult due to inconsistent analysis and reporting of variables that may influence results. For instance, as Michael Marco reported in the May 2001 TAGline (volume 8, issue 4), while HIV infection's tendency to accelerate hepatitis C disease progression has been well documented, it's less clear whether hepatitis C infection worsens HIV disease.

More recently, a number of studies have examined the effect of hepatitis C infection on immune reconstitution following the initiation of HAART. The touchstone for this debate is the Swiss HIV Cohort Study, which reported that co-infected patients showed a blunted immunological recovery on treatment which could not be attributed to poorer virologic response. A subset analysis of 56 co-infected subjects matched for baseline HIV viral load and CD4 count as well as age and sex found no correlation between HCV viral load and immunologic response, although genotype 3a was significantly associated with CD4 increases below 50 in the first year on potent antiretroviral therapy.

The interpretation of the subset analysis is complicated by the fact that 25% of the co-infected subjects had no detectable HCV viremia, implying a resolved infection. Some subsequent studies have found that despite comparable virologic responses, co-infected patients exhibit a diminished immunologic response to treatment as measured by gains in CD4 cells; others, however, report no immunologic differences.

This question has potential implications for treatment decisions, but a conclusive answer does not seem forthcoming. Some of the confusion relates to differences in study design. Three studies presented this year at the 9th Conference on Retroviruses and Opportunistic Infections illustrate this theme.

The ACTG 383 study (which added a retrospective component to a prospective study when the original trial failed to meet its target enrollment of 60 patients) found no differences in immunological response to HAART, following subjects out to 48 weeks; however, a Spanish prospective cohort study following clinic patients for 24 months found that impaired immunological recovery among co-infected patients becomes evident after the first year of HAART. A Thai analysis from the HIV-NAT trial also reported diminished immune reconstitution among HIV/HCV co-infected patients, although at 48 weeks there were no significant differences in risk of HIV disease progression.

A report from an observational study of the Frankfurt HIV Clinic Cohort also found that co-infected patients experienced CD4 cell increases of lesser magnitude, but qualified by noting that in their sample hepatitis C infection was closely linked to a history of injection drug use, which could be associated with another variable—the authors suggested adherence—that accounted for impaired immunologic response.

How should these divergent results be interpreted?
Co-infection studies—particularly those involving HAART—pose a potentially overwhelming array of confounding variables. In hepatitis C research, age, sex, degree of fibrosis, HCV viral load, race, genotype, and alcohol use can influence disease progression and/or response to treatment; various biochemical markers as well as quasispecies diversity may also play a role. HIV studies can incorporate variables including baseline CD4 count and viral load, nadir CD4 count, history of antiretroviral treatment, specific drug classes and regimens, adherence, and other more esoteric virological and host immunological factors such as phenotype and immune activation. None of the studies listed above considers all of these factors, nor could they; the resolution of such debates lies in identifying factors most likely to influence outcomes.

These lines of inquiry may ultimately lead us towards a less monolithic view of co-infection, as understanding of the interaction between the two viruses (and potentially hepatitis B virus and hepatitis G virus) and host responses continues to improve. It would be helpful to explore the possibility of identifying the varying patterns of co-infection based on rate of progression. Accelerated disease progression of one virus, or both might for instance, characterize a particular co-infection pattern, or neither until CD4 counts fall below a certain threshold. Such a classification system would have significant relevance to treatment decisions, but would ultimately require long-range cohort studies to better characterize the natural history of co-infection and the long-term clinical impact of various interventions. ¤