AIDS IN AFRICA: The Lazarus Effect - Pharmaceutical Executive

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AIDS IN AFRICA: The Lazarus Effect


Pharmaceutical Executive


A typical day in Kabalagala, outside Kampala
Uganda's capital, Kampala, is a city of more than a million people sprawled across the hills north of Lake Victoria. Central Kampala is busy and prosperous, with hotels and shops, embassies and—everywhere—the white, new SUVs of nongovernmental organizations (NGOs) emblazoned with acronyms that mostly include an "A" for AIDS. But go to the outlying districts and you are in another world: endless dirt-road slums with huts built of cast-off lumber, mud, and corrugated steel, no running water, and no sign of the NGOs or the assistance they've come to bring. One of the most desperate of these slums is Kabalagala.

On a Sunday morning at Pastor Paddy Luzige's New Life Church in Kabalagala, the congregation is made up disproportionately of children, many of them robbed of their parents by AIDS. More than 3,000 of the district's 16,000 residents are orphans, and Luzige, who with his wife Rose has adopted nine orphans, watches as group after group toddles in, the older children leading the brothers and sisters who have been left in their care. He seems to know them all by name.


Baylor College of Medicine's Sue Kelly, along with the pediatric ward staff at Mulago Hospital and a patient
The sermon today is about faith, and Luzige takes his text not from the Bible but from the clinic. He tells a story: Two people went for an HIV test. One was HIV positive, the other negative, but the clinic mixed up the test results. The man who was HIV-negative was told he was positive. He was devastated, lost his faith, and died. The other lived for a long time.

The rest of the service swells with joy and song, and many in the congregation linger long after the service is over. When they are gone, Luzige talks more about faith. With millions in Africa dying of AIDS—2.2 million in 2003, according to the Joint United Nations Program on HIV/AIDS (UNAIDS)—faith in God is all these people have.


A nurse dispenses medicines at a private clinic
What about treatment? What about the NGOs? What about drugs? Luzige gestures down the dusty streets, where the orphaned children gather. "There are no patients on AIDS drugs here."

It wasn't long ago when the same thing could be said almost anywhere in Africa. For people who work with AIDS in Africa, the change that occurs when drugs arrive has been almost miraculous. "When I came here in 2003, it felt like I was going back in time to the pre-protease inhibitor era," says Sue Kelly, lead project coordinator of the Baylor College of Medicine Pediatric AIDS Initiative at Mulago Hospital, the country's leading medical center. In those days, Mulago's pediatric AIDS clinic, formerly called Ward 15, operated one day a week out of a tiny, windowless room. There were four clinicians, but little they could do beyond watching children die. "Very, very few people in the entire country were on ARV [antiretroviral] treatment," says Kelly. "So it was just rooms full of very sick children here at the national public hospital. And now, we have been seeing people come back to life."


The Kabalagala Boys Choir educate audiences about AIDS prevention through song and dance
Many things count in controlling the AIDS epidemic. Diagnosis, education, and prevention are all crucial. But to achieve the transition Kelly describes, from watching people die to seeing them return to life, it takes drugs. And getting AIDS drugs to Africa, where patients are poor and the number of cases is unimaginably vast, is one of the great medical challenges of our time.

The latest step in responding to that challenge has been the program known as the President's Emergency Plan for AIDS Relief (PEPFAR), announced in President George W. Bush's 2003 State of the Union address and implemented, starting in June 2004—almost 25 years after AIDS was first diagnosed in Africa. Bush pledged $15 billion over five years to fight HIV/AIDS in 15 countries, mostly African. Much of the money is intended for grants to NGOs that fight AIDS. The first wave of cash focused on infrastructure initiatives, but as the program goes on, funds will increasingly go toward providing ARVs to AIDS patients.


A Ugandan man, whose sister and mother have died of AIDS
Uganda, one of the PEPFAR targets, is a good place to start in looking at what works and doesn't work in bringing AIDS drugs to the developing world. On the one hand, the country mobilized awareness and prevention efforts and political buy-in, resulting in grants not just from PEPFAR, but from the Global Fund to Fight AIDS, Malaria, and Tuberculosis (Global Fund), and the World Bank, as well as substantial investment from pharma companies. From 900 patients on ARVs in 2002, it now has an estimated 35,000 in treatment. "Implementation has been easier than we thought," says Amy Cunningham, HIV/AIDS advisor for USAID in Uganda.

On the other hand, though 35,000 patients on ARVs is a triumphant success, in a country with estimates ranging as high as one million HIV-infected patients and an 18-year-old war that threatens to make that number skyrocket, it is also a drop in the bucket. Uganda needs to have 60,000 patients on therapy by the end of next year, and more the year after that, if it is to have a sustainable defense against the epidemic. And getting drugs from the United States and England and Germany to Uganda is only the first step in the process. It's also a matter of getting the products from Kampala to Kabalagala and beyond, to the dying villages within the four kingdoms of Uganda.


Sowedi Muyingo, medical access
"Now the problem is not that we have the products available," says Helmut Leuchten, Boehringer Ingelheim's head of marketing for virology products. "Now we have to see how we can deliver the products, all of them, to the point where we need them.


Outside PEPFAR
For pharmaceutical companies, which have staked both dollars and reputation to clean up the world's biggest health disaster, the next few years will be crucial. Can Africa scale up its infrastructure to actually get drugs to the patients who need them? (That question becomes particularly important now that PEPFAR's $7 billion drug procurement and distribution program is on hold.) Can local caregivers achieve adequate compliance with drug regimens, not just to benefit patients but to help control resistance? As use of ARVs increases, will donated and preferentially priced products leak back into the US and European markets? And most important, how can the lessons of Africa be brought to bear as the AIDS pandemic moves to India, China, and beyond?

In the streets of Kabalagala, the orphans treat Pastor Paddy like an uncle or one of their lost parents. Perhaps in a few years he can preach a new sermon—not about faith and the botched test results, but perhaps this time a gospel story. Maybe he can tell them about Lazarus, who was dead and came back to life—and tell them that finally it's not a hope but a reality.

From the Ground Up

The infrastructure that distributes AIDS drugs in Uganda grew out of an UNAIDS initiative. From June 1998 through July 2000, UNAIDS ran a pilot program in Uganda called the Drug Access Intitiative (DAI), whose goal was to provide training, obtain ARVs from pharma companies at preferential prices, and set up a distribution system for them. The distribution system, Medical Access Uganda Limited (MAUL), has become an essential part of Ugandan healthcare. The goal of obtaining drugs at a discount was less successful. According to a report on Uganda by Oxfam International, the price of ARVs in Uganda in 2000 was about $1,000 a month—and that's in a country where the average adult earns about a dollar a day.

The situation improved as generics became available from Cipla in 2000, but also as the result of the Accelerating Access Initiative (AAI), a 2002 partnership between the United Nations and five pharma companies (Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffman-La Roche, and Merck) to reduce prices in selected developing countries. Prices for many ARVs in Uganda dropped by 50 percent or more, and the number of patients on therapy tripled at the Joint Clinical Research Center (JCRC), the national AIDS research center, which had pioneered the use of ARVs in Uganda in 1996.


3questions for Helmut Leuchten
To a US reader, the names and acronyms of agencies and initiatives may have the comforting sound of established bureaucracies. On the ground in Kampala, the reality is almost startling in its bare-bones simplicity. Take MAUL, for instance. To get there, you travel out the same road that leads to Kabalagala, and turn in the gate of the warehouse of the Joint Medical Stores, a religious not-for-profit supplier of pharmaceuticals. Upstairs, in a tiny office almost overwhelmed by two desks and a couple of filing cabinets, you'll find Sowedi Muyingo, PharmD, and his assistant. Through their hands pass 70 percent of brand-name antiretrovirals (and about 25 percent of all ARVs) that come into Uganda—$2 million worth of drugs in 2004.

"Far from rotting in warehouses," Muyingo explains, "there is a solid system for distributing drugs." Trucks carry shipments from Entebbe Airport to Medical Access, where they are unloaded and accounted for. The products then must go through a quality assurance check by Uganda's National Drug Authority, which takes samples of products before they are sold. Once the quality is assured, they are priced at a 2-5 percent mark-up to cover MAUL's costs and stored at the Joint Medical Stores warehouse.


Pharma Rhetoric?
Finally, the drugs go off to MAUL's clients: hospitals, clinics, and community based organizations (CBOs). Out front, there's a line outside the sales office of medical personnel waiting to pick up drugs (holding checks only, for fear of burglars), while from the fax machine spills an order from Dick Muhwezi, project manager of the ARV program for the AIDS Support Organization (TASO), the first and largest of the CBOs. With service centers located throughout the country, it provides substantial infrastructure and has allowed AIDS efforts to progress by moving treatment out of the hospital and into the community. Today, Muhwezi wants the usual first-line therapies—Combivir (lamivudine/zidovudine), Viramune (nevirapine), Sustiva (efavirenz), Zerit (stavudine), and Epivir (lamivudine)—for his seven centers accredited to provide ARVs. Because his headquarters is in Kampala, a two-story building renovated with a Pfizer grant, Muyingo arranges to deliver the order.

At TASO's office, Muhwezi demonstrates his inventory control system: a set of supply cards. He says the system works because the numbers are small—about 1,400 patients are on ARVs. But TASO is aiming for 3,000 patients by March 2005, and at some point the supply cards won't be enough.

"You can call me today and tell me, 'I really need nevirapine,'" says Muhwezi. "I will call Medical Access and I will get it tomorrow. But that won't be possible if I say, 'I need 1,000 boxes.' Now I need 100. Now I need 50. I can get those."


Pastor Paddy Luzige plays "football" with children at New Life Church's Saturday afternoon programs.
TASO is working with the US Centers for Disease Control to implement a new pharmacy information system that will enable Muhwezi to manage larger and more complex amounts of information. That will help TASO keep bigger stocks of ARVs at their headquarters and at the service centers—which will make for less disruption to the supply—and help better manage medicines' expiration dates.

What is less clear is how TASO will scale up the hard part of its job: taking drugs the final step from the CBO to the patient.

Into the Countryside To appreciate what the AIDS epidemic looks like, you need to go to the villages where the bulk of Ugandans make their homes—and where many city dwellers with AIDS come to die. Go, for instance, to Bukulula, a cough of dust in south Uganda, not far from Rakai, where the country's first AIDS case was diagnosed in 1982. It's a place where time passes slowly, mornings and evenings marked by the clockwork of children chewing sugarcane along the road, carrying water and firewood on their heads. But there's something really disturbing about this district—even for a country whose average life expectancy is hovering just over age 40, according to the Population Reference Bureau. There are few adults, a picture of what the mature epidemic will look like.

Here, Abdul Kakande, a registered nurse and one of the original co-founders of TASO's Masaka center, rides his boda-boda (Swahili for motorcycle), delivering drugs and care to patients too sick or too far away to make it to the clinic.

Kakande stops outside a clinic and meets up with Ssemwanga Godfrey, a "community nurse" for TASO. Community nurses are human infrastructure, put in place to run (and curb the costs of) very effective but very expensive home-based care. Godfrey closes his clinic/pharmacy to join Kakande in visiting TASO clients.

Innovative partnerships between the more established community organizations and grass-roots groups help providers overcome lack of resources. In Masaka, for example, the Ministry of Health coordinates TASO's efforts with Uganda Cares (See "Outside PEPFAR," ), Kitovu Mobile, a home care program focused on providing palliative care, and other providers to share doctors, counselors, and equipment.

The pair drive through Bukulula, passing trees filled with bananas, mangos, and passion fruit, before finally arriving at the patient's straw-thatched hut. The woman, who is co-infected with AIDS and tuberculosis (TB), sits on a feather filled mattress in the corner. She was expecting Kakande and Godfrey and has laid out her medications.

Her story is a familiar one: She lived in Kampala and was even buying ARVs at the JCRC. But when she could no longer afford to pay for the drugs, she stopped taking them and began to grow weak. She decided to to live with her sister in Bukulula so her children would be close to a caretaker. Before long, she was in the hospital, weighing only 66 pounds and with a CD4 count of three. (A normal count in a healthy, HIV-negative adult is usually between 500 and 1,500 CD4 cells per cubic millimeter of blood, according to AIDSmap.com.)

She was referred to TASO, which functions as the hospital's AIDS clinic, and, although close to death, she was put on ARVs sponsored by PEPFAR. She's on the first-line treatment regimen for AIDS patients with TB: Zerit, Epivir, and Sustiva. After five months of treatment, she says the drugs brought her back to life.

She says it was hard to follow the regimen at first, but TASO and Godfrey counseled her children and sister on how she should take the medication, which kept her compliant when she was too sick to know what day or night it was. Now, she says, it is second nature to her.

After the ARVs, she discusses the short-course therapy she's on for TB and the Septrin (cotrimoxazole) for prevention of opportunistic infections. She picks up the last bottle and pulls out the last pill, a pink, oval Diflucan (fluconazole), trade dressed for donations to differentiate it from the ones Pfizer sells in town. Kakande promises to get her more tomorrow, but says because of the restrictions on the Diflucan program, he can't leave it with Godfrey. However, he will leave it with her sister, who works close to TASO Masaka, to save him the trip back to the hut.

There are immense benefits to home care like this—not least, the way that it accommodates for patients who have children in a way that a hospital or clinic in the city never could. (The average Ugandan woman has between four and five children, a fact that adds a whole new layer of concerns to AIDS care.) But again, home care does not scale up easily or inexpensively, and there are both concerns and opportunities—especially in the area of prevention of mother to child treatment—for the role it will play in scaling up AIDS treatment.

As he leaves, Kakande hands her 10 individually wrapped oral hydration swabs, before marking the additional notes on the form. Her eyes light up—so many! Kakande responds, before getting back on his boda-boda, "God is good."

For Better or Worse AIDS care in Uganda in the next few years is likely to be defined by PEPFAR. The choices the Bush administration has made offer some real advantages to patients, but they also have serious drawbacks. First the good news:

Proven drugs. The US government stipulates that only FDA approved drugs can be used in PEPFAR-funded programs. Therefore, the use of ARVs in those projects are based on tried and true clinical practice guidelines with proven outcomes—which is especially important for children.

"Up until PEPFAR-funded activities started, Mulago was using a lot of generics," says Mark Kline, director of the Baylor International Pediatric AIDS Initiative, which helps operate the pediatric AIDS clinic at Mulago, among several other pediatric AIDS clinics. "Many of the fixed dose combinations (FDCs) were only available in adult formulations, so clinicians were halving and quartering pills without any documentation that this made sense pharmacologically. Even if the brand-name drugs are more expensive, we should still use the drugs where we have all of the data and we know that if they are used correctly, they will achieve the desired results."

Certainly, the de-listing of several generic ARVs from the World Health Organization's prequalified list in recent months, including medicines from Cipla, Ranbaxy, and Hetero Drugs, cause some to believe that generics have the potential to sabotage growing treatment efforts. After all, the World Bank had already procured and distributed the de-listed generics for 2,700 patients through the Multi-country AIDS Project (MAP).

"It is extremely disappointing," says Peter Nsubuga, MD, MAP project manager. "But you end up having to continue the treatment—we cannot take back the drugs that we have already procured. So we shall proceed, I guess. We shall proceed and finish the drugs and then make new plans."

Less diversion. One clearly good choice PEPFAR made was to work through MAUL instead of through the system the Ugandan government uses, the National Medical Stores (NMS). Previous programs haven't been as lucky: In 2002, fluconazole pills donated by Pfizer to the government of Uganda—and intended for distribution through NMS to health facilities—were diverted and ended up for sale on pharmacy shelves. And in 2003, NMS tried to sell GSK-supplied Combivir to a local company, Eris, which was a buyer for Landmark Pharmaceuticals, which was then free to sell the products at profit to other markets. MAUL, to date, has had no similar problems.

It's working. Finally, PEPFAR proponents say, although the system isn't perfect, it is already operational—unlike the Global Fund grants that were promised in 2002 but have not yet been dispersed. "It is not bogged down by bureaucracy," says Emmanuel Luyirika, the medical director of Mildmay Centre, a specialist outpatient referral center set up by international donors for people with HIV/AIDS. "The system PEPFAR uses is much faster than the government system. In fact, the PEPFAR program is the one that has made the biggest impact in our city here, in terms of free care. Within six months, we already have 700 patients on ARVs. We hope by the end of March 2005, we will have about 1,400 receiving free care through PEPFAR. That is our only source of free ARVs."

On the negative side:

US money for US drugs. Despite the MAP debacle, there is a rising resentment toward the Bush government for refusing to purchase generic ARVs. That sentiment is being fueled by providers as they gain experience with generics and report good results and as more data about generics becomes available. One example is the Médecins Sans Frontières (MSF) study published in the Lancet that found Cipla's FDC Triomune performed as well as brand-name drugs.

"Bilateral plans are turning into a slush fund for Big Pharma," says Asia Russel, coordinator for international policy at HealthGAP, a US-based activist organization.

Parallel systems. PEPFAR's separate and specialized distribution system doesn't support most countries' national scale-up strategies and works outside the Ugandan healthcare system. That's causing confusion inside clinics among physicians and other providers, who must keep funding sources, patients, and pills separate.

"In Rwanda, where we have both MPTCT Plus programs and PEPFAR-funded programs at the same clinic, there's stress that the two different sources look different," says David Hoos, MD, assistant professor at the Columbia University Mailman School of Public Health, and chair of the Global Fund's procurement advisory panel. "They have to keep the stock in separate places so that the parallel system causes distress at the clinical level and it confuses patients. Because they don't know that there are different funding sources and different products, they are asking: 'Why does my drug look different than this person's drug?'"

Not uplifting general system. Nsubuga, who uses NMS to distribute the World Bank's ARVs, says PEPFAR grants also do nothing to uplift, strengthen, and expand the general medical care system, which is collapsing under the weight of the epidemic. Although PEPFAR money is only awarded to programs focused specifically on HIV, the prevalence of AIDS in Uganda (estimates peg it anywhere from 4.1-17 percent) is such that the disease affects all aspects of healthcare—from general practitioners to TB wards. In addition, PEPFAR-funded programs attract the country's skilled manpower with high salaries, which further detracts from the Ugandan system and will have implications when PEPFAR disappears in 2008.

From Infrastructure to Price The pharma industry has been a moving target in the AIDS epidemic. "The debate has gone from being one of patents that kill to prices that kill, to where it is now, which is much more about the whole area of lack of healthcare infrastructure," says Jon Pender, director of external relations, global access issues for GlaxoSmithKline.

But that focus may soon change again. Bush has touted PEPFAR's goal of supporting two million people on treatment in the focus countries. But the US Government Accountability Office, in a recent report, says that it doesn't know how much that will cost, given the uncertainty, as the plan progresses, about price and which drugs will be included.

The establishment of crucial infrastructure will also compound the focus on price. But this time around, the discussion over price will become more sophisticated, evolving beyond just generics and brands.

Beyond generics. FDA approved its first generic ARV—co-packaged versions of nevirapine tablets and a pill combining lamivudine and zidovudine—through its expedited review process. Boehringer Ingelheim and GSK licensed those products to Aspen PharmaCare through settlement agreements reached in the 2001 court case against South Africa. That means organizations can now buy generic ARVs with PEPFAR funds—as long as patent holders give their approval. But the FDA approval is also significant because it recognizes the emerging category of "high-quality generics."

Other issues point to the further blurring of the line between brand-name and generic drugs. A triple fixed-dose combination, like Triomune, is not a true generic because there is no brand-name equivalent. And the co-packaging agreements of branded products now on the horizon are without precedent.

More competition. The new products from Aspen, the $4 billion in funds PEPFAR specifically earmarked for procuring and distributing treatment, and the general trend of companies relying on individual strategies, instead of AAI, to reduce prices should create more pressure on price.

"Depending on the quantities," says Muyingo, "you might be able to get a deal. It also helps to bring companies against each other. Roche, for example, reduced some of their prices after we told them that, compared to the others, they are very expensive."

Already, some brand-name products (like Zerit) are less expensive than generics. That may have to do with Merck's strategy of individual country pricing, compared with the industry standard of setting one preferential price for the entire developing world. "Merck includes a couple of different criteria, like human development index and HIV prevalence, when they price their medicine," says Rachel Cohen, US director of the campaign for Access to Essential Medicines for MSF, which also runs a small ARV program in the embattled north of Uganda. "Their prices may still be too high, but at least they are transparent. None of the other companies have done that so far."

Pharma-sponsored programs. Other companies have chosen to sponsor programs that don't reduce prices per se, but do increase access. It's hard to mention Uganda without noting the sizeable investment Pfizer has staked in the country. Not only does it donate Diflucan, a prime weapon for fighting opportunistic infections, but Pfizer has also paid for a new medical center, which will likely train the healthcare provider who will deliver that donation.

BI also donates Viramune to Uganda as part of a larger effort to offer the product free of charge to 57 countries for the prevention of mother-to-child transmission of HIV. "I don't think it will come down in terms of price per tablet," says Leuchten. "But we will do more in terms of supporting the people with efforts to improve the supply chain and treatment education."

Smaller programs are also at work. GSK, for instance, gave a grant to the Uganda Business Coalition on HIV/AIDS (UBC) to open a workers treatment center (WTC) in 2003. That was the first center established to engage the private sector and focus on treating the infected working population. "Member companies pay a fee to the UBC, then their employees get subsidized treatment and tests and free consultation," says Dickson Opul, MD, UBC executive director and former Merck country manager for Uganda.

These pharma-sponsored programs offer tangible benefits. BI's program spurred Abbott to donate its HIV rapid-test Determine, and together they created a foundation in which countries could piggyback additional care services. And the WTC helped establish new models of treatment for the working population that is the hardest hit by the disease. But those gains haven't been without lessons: countries complained that BI's PR around the donation—which was slow to ramp up because of low rates of testing—outstripped the donation itself. And though the GSK funding allowed the WTC to subsidize ARVs, the funding eventually stopped, driving prices back to normal levels so that some patients were forced to stop taking the drugs.

Outreach for All Inside a dark hut, a father sits by his son, both infected by the disease. The pair try to sit up, their struggle only partially shrouded by a curtain. The lesions are apparent. So is the thrush—big white sores that dot their tongues, making it hard to eat. Their limbs are weak, their bodies speckled by bedsores.

They used to receive help from St. Francis Nsambya hospital, a local religious institution. Health workers brought medication to treat opportunistic infections along with porridge and sugar. But a few months ago they stopped. Maybe their funding dried up. Maybe they just had too many patients of their own. No one seems quite sure.

Nsambya Hospital received a small PEPFAR grant in 2004, enough to put 164 adults and 24 children on ARVs, says Pastorali Katwebaze, director of the AIDS Widows Orphans Family support program at the hospital. But Nsambya serves more than 100,000 people in the poorest sections surrounding Kampala. That translates to 4,000 AIDS case—or more likely 15,000 or 20,000. Multiply that by the number of districts in Uganda, by the number of countries in Africa, and you begin to understand the issues still facing the scale-up of PEPFAR.

Pastor Paddy Luzige prays with the father and son—using his one infinitely renewable source of hope. When he leaves, the sick are still sitting, still waiting. Maybe tomorrow.

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