Advertisement
The Body: The Complete HIV/AIDS Resource
Follow Us Follow Us on Facebook Follow Us on Twitter Download Our App
Professionals >> Visit The Body PROThe Body en Espanol
  
  • Email Email
  • Printable Single-Page Print-Friendly
  • Glossary Glossary

TAGline/Volume 5 Issue 2

March 1998

Contents:

  1. CDC/Thai Vertical Transmission Results Silence Critics and Pave Way for Prevention of Millions of Infections Worldwide
  2. Comparing the Two Regimens (Table)
  3. Long Languishing in Shadow of the Antiviral Quick Fix, Immune Based Therapies Are Called to Center Stage

Swift Success

CDC/Thai Vertical Transmission Results Silence Critics and Pave Way for Prevention of Millions of Infections Worldwide

But who will bear the cost?

Four years ago, results of ACTG 076 showed that HIV-infected pregnant women treated with a complex regimen of AZT (100 mg five times daily during the third trimester of pregnancy, intravenous AZT (1 mg/kg/hour) during delivery, and oral treatment of the newborn infant (2 mg/kg every 6 hours) for the first 6 weeks of life) could cut the rate of maternal-fetal HIV transmission by two-thirds (from 22.6% to 7.6%). This regimen, however, is prohibitively expensive -- about $800 per patient -- and largely unrealistic in many developing-world settings where pregnant women often do not enter the healthcare system until late in pregnancy and where delivery rooms may lack the capacity to deliver intravenous medication. Now, results from a controversial AZT-vs.-placebo study conducted in Thailand have shown that a much less onerous (and less expensive) preventive protocol can produce nearly the same results. Spencer Cox reports.

Around the globe, more than 1,600 infants are born infected with HIV every day. And without effective preventive therapy, 5-10 million children will become infected with HIV through perinatal transmission before the year 2000 -- 90% of them in the so-called developing world. But it is precisely in these impoverished countries hardest hit by HIV that the potential of the "076 regimen," as it has come to be called, has been least realized.

In an attempt to address this reality in the wake of the 076 results, officials from the World Health Organization (WHO), the United Nations, the National Institutes of Health (NIH) and the Centers for Disease Control (CDC) gathered in Geneva in June 1994 to design perinatal transmission trials suitable for the developing world. In the absence of any standard of care, they settled on comparing different courses of AZT to placebo. Almost from the outset, there was controversy. Since that time, 18 randomized, controlled trials of interventions to prevent perinatal HIV transmission have begun which are to evaluate a variety of interventions: antiretroviral drugs such as AZT (usually in regimens less expensive or complex than the ACTG 076 regimen), vitamin A and its derivatives, intrapartum vaginal washing, and HIV immune globulin. These trials involve a total of more than 17,000 women from the following countries: Ivory Coast, Uganda, Tanzania, South Africa, Malawi, Thailand, Ethiopia, Burkina Faso, Zimbabwe, Kenya and the Dominican Republic.

Advertisement
Last month, the first of these studies (co-sponsored by the Ministry of Public Health of Thailand and the U.S. Centers for Disease Control and Prevention) to produce results was completed in Thailand where a short course of orally administered AZT given during the last 3-4 weeks of pregnancy was reported to result in a 50% reduction in the rate of mother-to-infant HIV transmission (from 18.6% to 9.2%). The MOPHT/CDC study marks a watershed in the ability to begin controlling HIV transmission in regions where more costly, lengthy antiretroviral courses are simply not feasible. The regimen used in the Thai study costs an estimated $50-$80 per patient -- or less than one tenth the cost of the 076 regimen. These results should lead to the immediate provision of AZT to all HIV-infected pregnant women who wish to use it to interrupt vertical transmission anywhere in the world.

While a 50% reduction in infection rates is impressive, many AIDS researchers and activists believe that new studies suggest the potential for still more effective means of preventing vertical HIV transmission. On-going studies looking at combinations of relatively inexpensive drugs, such as nevirapine and lamivudine (3TC), for example, are likely to show even greater potency. The use of AZT in pregnancy also carries with it at least the theoretical risk of rare long-term side effects in the infant. Once the drug becomes routinely prescribed for millions and millions of HIV-infected pregnant women, little-reported side effects could emerge which have not been seen among the comparatively small number of women-infant pairs treated in industrialized nations. While high-doses of AZT administered to pregnant mice have been shown to cause tumors in the liver, lung and genital tract of their offspring, AZT doses which are believed to more closely replicate the 076 regimen have not resulted in an increased cancer risk.

A number of vertical transmission studies in the developing world, including the MOPHT/CDC Thai study, have been criticized by New England Journal of Medicine editor Marsha Angell and by the consumer advocacy group Public Citizen. "The Declaration of Helsinki requires control groups to receive the 'best' current treatment, not the local one," Angell wrote in a September 18th editorial. "The shift in wording between 'best' and 'local' may be slight," she continued, "but the implications are profound." Public Citizen's Peter Lurie and Sidney Wolfe protested to Health and Human Services secretary Donna Shalala and argued that it would be just as scientifically valid -- albeit more expensive -- to compare a short course of AZT to the longer 076 regimen. Alongside Angell's New England Journal editorial they cautioned that, "Residents of impoverished, post-colonial countries... must be protected from potential exploitation in research. Otherwise, the abominable state of health care in these countries can be used to justify studies that could never pass ethical muster in the sponsoring country."

Critics charged that the use of a placebo control was ethically comparable to the Tuskeegee syphilis experiment, in which therapy for syphilis was withheld from a group of impoverished black men so that scientists could observe the natural history of the disease. Supporters of the placebo control, however, argued that use of a placebo was the fastest, most efficient way to obtain unambiguous information that would be of greatest value in the Third World -- and to identify regimens that were likely to be less effective than the 076 regimen. Dr. Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania (who argued against the placebo design), says the Tuskegee analogy is inappropriate if only because the Alabama men were falsely told that they were getting treatment. The New England Journal controversy led to the resignation of AIDS experts Dr. David Ho and Dr. Catherine Wilfert from the Journal's editorial board.

But without the placebo control we might have never known that short-course AZT is effective -- and whether the treatment is doing more harm than good. Over 500,000 infants are born with HIV each year. And now -- just over one year after the trial began -- we know that short-course AZT has the potential to prevent HIV infection in at least half of these cases -- saving millions of lives in the next few years. Placebos are needed no longer -- in this or any of the other on-going mother-infant transmission studies. In fact, in the second of the two CDC/UNAIDS collaborative perinatal HIV transmission studies (being conducted in Abidjan, Ivory Coast), all pregnant women previously receiving placebo have been offered the short-course AZT regimen.

Given these stunning study results, Glaxo-Wellcome should begin to make AZT available to poor countries for a substantially reduced price -- or give the drug away for free, as Merck did with its drug for African river-blindness. While the new, short-course regimen costs only one-tenth what the 076 regimen costs, this is still approximately eight times what most developing nations spend annually on health care per patient. It is clear that only a cooperative venture between local governments, the World Health Organization, private industry and advocates for people with HIV/AIDS will allow us to gain maximum benefit from these important findings.


Comparing the Two Regimens
 
076 Short Course
Prepartum Oral AZT 100 mg/q5h final 12 weeks of pregnancy Oral AZT 250 mg/BID last 3-4 weeks of pregnancy
Intrapartum I.V. AZT 1 mg/kg/hr until delivery No treatment
Postpartum AZT syrup to newborn 2 mg/kg q6h for 6 weeks No treatment
Risk of Transmission 7.6% 9.2%


Immunization to the Fore

Long Languishing in Shadow of the Antiviral Quick Fix, Immune Based Therapies Are Called to Center Stage

How to refortify the immune system

The twilight of eradication may herald a new dawn for HIV immunology research, which has been largely overshadowed by advances in antiretroviral therapy over the past three years -- and its now haunting mantra of, ‘It’s the virus, stupid.’ At a recent meeting at Robert Gallo’s Institute for Human Virology (IHV), 60 HIV immunologists from the U.S. and Europe enthusiastically looked forward to 1998 as the year of the return to the immunocentric disease modeling that characterized mainstream HIV research during the 1980s and early 1990s. Craig Sterritt prepared this report for TAGline.

The meeting, entitled "Immune Function and Surrogate Markers: Setting the Goal Line," was charged with taking stock of the current state of HIV immunology and immune-based therapy (IBT) research and charting the course ahead for the development of new therapeutic interventions. Key to the evaluation of new immune-based therapies is the identification of surrogate markers useful in evaluating the biologic activity(ies) -- and clinical efficacy -- of the therapies in question. Appropriately, Robert Siliciano convened the scientific sessions with a review of his recent findings concerning the "third compartment" of viral decay -- namely, long-lived, quiescent memory T-cells harboring integrated HIV DNA. Many feel that Dr. Siliciano's reports, along with corroborating ones from other labs, have put the kibosh on the timely eradication hypotheses promulgated by David Ho and others. In essence, it now seems unlikely that HAART will be able to effect viral eradication within 10 years -- let alone 2 or 3.

Although the new highly active antiretroviral regimens may not result in viral eradication, longitudinal immunophenotypic and functional studies have demonstrated that they can lead to marked improvements in diverse parameters of immunocompetence. Two groups -- one led by Brigitte Autran in Paris and the other Michael Lederman of Case Western Reserve in the U.S. -- have been looking at what happens to the immune system following the initiation of HAART. They are finding that the immune systems of people who achieve and maintain undetectable viral loads on HAART gradually begin to normalize and look more like the immune systems of HIV-negative people and HIV-infected long-term non-progressors (LTNP). Specifically, T-cell counts go up, markers of immune hyperactivation diminish, and T-cell subsets, including CD4+, CD8+, memory and naïve T-cells, each type of which is disproportionately either increased or reduced during HIV infection, trend toward a more normal state. These effects are believed to be the immunologic correlates of HAART's clinical effects: increased resistance to infections, reduced disease progression, and improved survival.

Most significantly, Dr. Autran reported the recovery of previously 'lost' cellular immune responses to recall antigens (i.e., specific pathogens, such as mTB). Dr. Fred Valentine of NYU also reported the return of immune reactivity to Candida and other recall antigens in some patients receiving HAART. Citing an example of a patient with undetectable T-cell responses to PCP who experienced PCP after discontinuing prophylaxis consecutive to substantial CD4+ T-cell increases on HAART, Dr. Valentine suggested that the immunologic yardstick used to measure these responses -- the lymphocyte proliferation assay (LPA) -- may be a useful clinical tool for determining whether to continue or stop prophylaxis for particular infections in individual patients. Additional studies of this immunologic marker will be required, however, as Dr. Lederman presented evidence that improved LPA responses to recall antigens may be transient. His group observed improved antigen-specific LPA responses after 12 weeks of HAART, but noted no significance difference from baseline at 48 weeks.

Even with the return of improved general and pathogen-specific immunity, what has been observed to date can only be referred to as partial immune reconstitution. This is because in some cases (but not all), when HAART stops working, the immune system rapidly reverts to its pre-HAART state: T-cells decline and other immune markers become skewed again -- i.e., HIV disease progression continues. Although HAART can provide the immune system with a period of significant recuperation, this temporary cease fire apparently does not lead to improved HIV immunity. As Dr. Autran explained at the IHV meeting, even after 2 1/2 years, her studies have yielded no evidence that HAART can restore immune responses associated with improved control of HIV, such as those seen in HIV-infected LTNP (e.g., detectable LPA responses to p24 antigen; see TAGline, January 1998).

With regard to full immune reconstitution, what could ideally be accomplished is that new (immune-based) therapies could be used to refortify patients' immune systems against HIV and other pathogens while their HIV levels are being suppressed by HAART. In this way, if HIV returns -- if people on HAART experience "virologic failure" -- patients' immune systems would be better equipped to control HIV in the presence of waning antiretroviral efficacy. If we position contemporary IBT research within this context, HAART may be seen to provide a window of opportunity during which optimal host immunity to HIV (and other pathogens) may be restored. As Dr. Valentine succinctly stated at the IHV meeting, "my definition of immune reconstitution is bringing back an immune system that can respond to and better control HIV."

It is possible that immune reconstitution defined as such can occur, at least to a moderate degree, in some people treated with HAART. It is clinically apparent, although the phenomenon has not been captured in either Dr. Autran's or Dr. Lederman's studies, that some people who "fail" HAART continue to do well immunologically and clinically. These cases are typified by stable or increasing CD4 counts in the presence of virologic breakthrough, wherein viral load becomes detectable but does not return to pretreatment levels. It is entirely unknown why this occurs, what the immunologic basis for it is, or whether such an anomalous rising viral load/rising T-cells state is durable. It is possible, however, that the situation marks an advanced degree of immune reconstitution achievable with HAART, but as yet unelucidated by clinical studies. Dr. Valentine and others are eagerly recruiting immunologically stable/virologic breakthrough patients in order to characterize potential immunologic determinants of this phenomenon (see footnote below).

With regard to therapeutic interventions, the future of IBT research in HIV disease will concentrate on the induction of potent anti-HIV and anti-OI immune responses in patients who experience partial immune reconstitution on HAART. Immediate research is focusing on the use of therapeutic vaccination with HIV antigens. As TAGline reported in January, strong anti-HIV CD4+ LPA responses have been documented in monkeys inoculated with a DNA vaccine. A preliminary clinical study has demonstrated that this approach is safe for use in humans. At the IHV meeting, Ron Moss of Immune Response Corporation reported that vaccination with the "Salk" HIV-1 immunogen induced strong CD4+ LPA responses to the immunogen itself and to purified p24 antigen derived from the immunogen. Cross-clade (clades B and E) anti-HIV LPA responses were also documented in a small study by Dr. Moss and colleagues. In addition, Dr. Moss reported significantly increased p24 antigen-induced beta-chemokine production (RANTES, MIP-1alpha and MIP-1beta) following immunization with the Salk HIV-1 immunogen. Finally, a team of NCI researchers have announced the development of an inactivated HIV immunogen that retains the structural and functional properties of HIV's envelope proteins. All told, numerous groups around the world are preparing to begin vaccinating HAART-treated patients with HIV antigens and/or anti-OI antigens. Initial trials will focus on the ability of interventions to induce or augment antigen-specific LPA responses, cytotoxic T lymphocyte responses, and beta-chemokine release.

What remains to be fully elucidated is how improvements in specific immunologic tests (such as those cited above) can be used to predict the clinical efficacy of a therapeutic intervention. In spite of its go-getter title, "Setting the Goal Line" did not effectively push forward the cause of identifying expedient methodologies for qualifying and quantifying immune reconstitution. To date, the only immunologic marker that has been validated as a surrogate for clinical efficacy is the CD4+ T-cell count.


There was conjecture at the IHV meeting that these anecdotal reports may be found to reflect the recovery of robust anti-HIV cellular immune responses, such as those seen in LTNP and in acute seroconverters treated with HAART by Bruce Walker and colleagues at Harvard and Mass General (see TAGline, January 1998). These responses -- namely, CD4+ T-cell proliferative responses to HIV antigens -- are typically lost soon after initial infection. Conventional wisdom maintains that this is a consequence of the preferential elimination of activated anti-HIV CD4+ T-cells by HIV during the earliest phases of infection, and that this 'clonal depletion' is manifest as pertubations in the T-cell repertoire. Theoretically, it is possible that with long-term suppression of viral replication, immune normalization may extend to include the correction of biases in the T-cell repertoire. This would occur as naïve T-cells, with the capacity to engender new clones of potent anti-HIV T-cells, return to the blood and tissue of people with HIV. Both Dr. Autran and Dr. Lederman have reported quantitative and proportional increases in naïve T-cells following prolonged suppressive antiretroviral therapy. Indeed, Dr. Autran has documented some degree of correction in the T-cell repertoire, although the immunologic and clinical significance of these findings remains unclear.





  
  • Email Email
  • Printable Single-Page Print-Friendly
  • Glossary Glossary

This article was provided by Treatment Action Group.
 

Tools
 

Advertisement