Amprenavir Solution Warning Issued

In early May, Glaxo Wellcome issued a warning about the oral solution of its protease inhibitor (PI) amprenavir (Agenerase). The oral solution contains propylene glycol, which some people cannot tolerate. Children under age four, pregnant women, people with liver or kidney failure, and Asians and Native Americans may in particular have trouble metabolizing and eliminating the substance, allowing it to accumulate to toxic levels in the body. This may result in symptoms including seizures, stupor, increased heart rate, and kidney failure.

Glaxo said that only people who can not use the capsule formulation of amprenavir should use the oral solution, and that people who use the oral solution should not drink alcohol.

FDA Approves New Nelfinavir Formulation

In March, the Food and Drug Administration (FDA) approved a new film-coated formulation of Agouron Pharmaceuticals' PI nelfinavir (Viracept). The new formulation is designed to reduce premature dissolving or breaking of the tablets. The dosage contained in one tablet will remain the same. Twice-daily dosing was recently approved for the drug.

Expanded Access for Liquid Efavirenz

In April, DuPont Pharmaceuticals announced an expanded access program for the liquid formulation of its non-nucleoside reverse transcription inhibitor (NNRTI) efavirenz (Sustiva). The program will be run as an open-label, multi-site study for children and adolescents aged 3 to 16. Treatment-naive children will be given efavirenz plus two nucleoside analogs (NRTIs), while children who have experienced treatment failure on their existing regimen will receive efavirenz plus an NRTI and a PI that they have not yet used.

Efavirenz will be provided for free for participants in the study. DuPont is expected to apply for approval of the liquid formulation later this year. For enrollment information,
physicians may call 877-372-7097.

Better Immune Recovery and Drug Response in Teens

Research published in the April issue of the Archives of Pediatrics and Adolescent Medicine suggests that adolescents with HIV are better able to fight the virus than younger children or adults, and may respond better to anti-HIV treatment.

Steven Douglas, MD, and colleagues from the University of Pennsylvania and the Adolescent Medicine HIV/AIDS Research Network reported that teenagers aged 13 to 18 regenerated more naive CD4 T-cells and "killer" CD8 T-cells than younger or older people, indicating that teens' "more robust" immune systems may be more capable of reconstitution following anti-HIV therapy. Naive T-cells are not yet committed to fighting a specific pathogen, and thus can be called into action when a new invader is encountered. According to Dr. Douglas, adolescents "may have the best chance of having their immune systems bounce back" after treatment.

The explanation may lie in the fact that teenagers usually still have a functional thymus gland, an immune system organ in which T-cells reproduce and mature; the thymus is active in children, but deteriorates and becomes less active in adults.

HLA Variant Protects Long-Term Nonprogressors

Researchers reported in March that a specific immune system gene might protect certain long-term nonprogressors (LTNPs) from developing AIDS. TNPs are HIV positive people who have remained symptom-free much longer than expected.

A team from the National Institutes of Allergy and Infectious Diseases (NIAID) examined human leukocyte antigen (HLA) variants in 13 people who had been HIV positive for 15 years but still had a normal CD4 count and a very low viral load. HLA is a protein that attaches to pieces of a pathogen (antigens) inside an infected cell and transports them to the cell surface, where they can be recognized by T-cells. HLA proteins vary from person to person, and some HLA variants seem better able to attach to HIV antigens. In this study, 11 of 13 (nearly 85%) of the LTNPs carried the HLA variant B*5701; this variant occurred in only 9.5% of people who had progressed to AIDS.

The study results suggest that a feature of the immune system -- rather than a weakened viral strain -- may explain why some people with HIV do not develop AIDS. The research was published in the March 14, 2000 issue of the Proceedings of the National Academy of Sciences.

In related news, Ricky Bluthenthal, PhD, and colleagues from RAND in San Diego reported in the March 31 issue of AIDS that injection drug users who use a syringe exchange program are more than two times more likely to stop sharing needles than those who do not make use of such a program. The four-year study included 340 "high risk" injection drug users. Sixty percent of those using a needle exchange reported that they stopped sharing.

Heterosexual Transmission Linked to Viral Load

Viral load is the most important factor influencing heterosexual transmission of HIV, according to research published in the March 30 issue of the New England Journal of Medicine.

A research team from NIAID, Johns Hopkins University, Columbia University, and Makerere University in Uganda followed 415 serodiscordant heterosexual Ugandan couples for 30 months; one member of each couple was HIV positive while the other was HIV negative. Over the course of the study, 90 (22%) of the initially HIV negative participants seroconverted. Participants were provided with condoms and educational materials, but the researchers did not inform the HIV negative partners that their spouse carried the virus.

The researchers found that HIV RNA viral load levels were higher in the HIV positive participants whose partners contracted HIV than in those whose partners did not seroconvert. No transmissions occurred in participants whose partner had a viral load below 1,500 copies/mL. According to lead investigator Thomas Quinn, MD, "with every 10-fold rise in concentration of HIV in the bloodstream, transmission more than doubled."

This study found similar male-to-female and female-to-male transmission rates; in several previous studies, the male-to-female rate was significantly higher. In addition, seroconversion rates in this study were higher in those aged 15 to 19, and only men who were uncircumcised contracted HIV, although the influence of circumcision and the presence of other sexually transmitted diseases was minimal compared to the influence of viral load.

Advantage Microbicide Shown Ineffective against HIV

In June, researchers reported that a nonoxynol-9 microbicide/spermicide failed to prevent the transmission of HIV in women in a UNAIDS-sponsored study.

The microbicide, Advantage-S, was being tested in Phase III trials involving 700 female prostitutes in developing countries including South Africa and Thailand. Half of the women received Advantage-S vaginal cream and half received a placebo cream; all were supplied with and encouraged to use condoms as well. The trial was halted after 100 of the women contracted HIV.

Researchers found that the women using the microbicide actually contracted the virus at a slightly higher rate than those using the placebo, a result the researchers called "bewildering."

Activists Demand Fair Pricing of Lopinavir and New ddI

The Fair Price Working Group, a coalition of AIDS treatment activists and advocacy groups in April called on Bristol-Myers Squibb (BMS) and Abbott Laboratories to rein in prices for two new anti-HIV drugs, BMS's new enteric-coated formulation of ddI (Videx) and Abbott's new PI lopinavir (ABT-378).

The advocates warn that anticipated high prices for the drugs could threaten government programs that pay for AIDS drugs, such Medicaid and California's AIDS Drug Assistance Program (ADAP), and could set off an industry-wide round of drug price increases. The coalition fears BMS will set the price for enteric-coated ddI as much as 40% higher than the price for standard ddI, which has been on the market for a decade. The coalition maintains that "neither [drug] represents a major advance in therapy."

According to a consensus statement signed by numerous individuals and groups, "As drugs become available which might facilitate better adherence and possibly more durable long-term treatment, manufacturers should be planning to lower or at least contain the daily cost of their regimens, not increase them."

Further, the statement said, "Exploitative pricing will trigger widespread mistrust, contentious debate, and closer scrutiny of industry practices in general, and give comfort to those who think that AIDS is simply a scam designed to line the coffers of the pharmaceutical industry."

Pharmaceutical companies typically claim that high prices are necessary to allow for future drug development; drug company profits are consistently among the highest of any industry.

Clinton Declares AIDS a National Security Threat

On April 30, President Clinton formally declared AIDS a threat to national security. The announcement follows a National Intelligence Estimate released in January suggesting that developing countries heavily impacted by AIDS could face a "demographic catastrophe" which could reduce life expectancy, undermine economic development, increase poverty, encourage civic unrest, set off revolutionary and civil wars, undermine militaries, and destabilize governments. The administration requested $254 million -- roughly double the previous budget -- to combat AIDS outside the U.S.

According to Sandra Thurman of the White House Office of National AIDS Policy, "We have to respond to this because we've never seen a crisis like HIV and AIDS globally. We're beginning to understand that this epidemic not only has health implications, but has implications as a fundamental development issue, an economic issue, and a stability and security issue."

Some critics of the administration's announcement declared that it was a case of "too little, too late," while others said that it was not an appropriate way to deal with a public health issue.

Global Drug Pricing and Access

On May 10, five major pharmaceutical manufacturers -- Boehringer Ingelheim, Bristol-Myers Squibb, Glaxo Wellcome, Merck & Co., and Roche Holdings -- announced that they would cut anti-HIV drug prices for people in poor countries by as much as 90%. The move comes in the wake of efforts by several developing countries to license or manufacture cheaper generic versions of patented drugs.

Glaxo said it would lower the cost of its drug Combivir (AZT/3TC) to $2 per day, about a fifth of the drug's current U.S. price.

Peter Piot, MD, of UNAIDS said, "It's the first time the companies are collectively willing to discuss a truly significant decline in prices. It is something many of us have hoped for."

However, critics of the plan say that even the reduced-price drugs will be prohibitively expensive for developing countries. Bernard Pecoul of the international medical aid group Médecins Sans Frontières/Doctors Without Borders said, "The reality is that despite this initiative, AIDS drugs will still be unaffordable for the vast majority of those in need in the poorest countries."

On the same day, President Clinton signed an executive order stating the U.S. would not oppose efforts by countries in Sub-Saharan Africa to import or produce less expensive local versions of patented anti-HIV drugs. The move came a week after legislators removed a similar provision from the African Growth and Opportunity Act trade bill.

Clinton announced last December 1 -- in the midst of massive protests in Seattle against the World Trade Organization -- that he would relax U.S. trade rules concerning patented drugs, saying, "The U.S. will henceforth implement its health-care and trade policies in a manner that ensures people in the poorest countries won't have to go without medicine they so desperately need."

Some activists contended that the president's announcement did not go far enough. Paul Davis of ACT UP/Philadelphia criticized the executive order for only covering anti-HIV drugs and only being applicable to Sub-Saharan Africa. "There are more killers than HIV/AIDS," he said, "and lots of folks who have AIDS in other countries."

Alan Holmer, president of the Pharmaceutical Research and Manufacturers of America, said that Clinton's executive order set "an undesirable and inappropriate precedent."

In related news, in Thailand a state-run drug manufacturer in June began producing a cheaper, generic version of d4T (Zerit); the generic drug will sell for 28 to 38 cents per tablet, compared to about $2.60 per tablet in the U.S.

Page last updated 16 August 2000