American Foundation for AIDS Research, July 2002
Anne-christine d'Adesky

Introduction

Only 5% of those who require HIV therapy have access to it in developing countries. The World Health Organization wants to multiply that figure tenfold over the next three years, so that three million people receive treatment. Its officials have just issued draft treatment guidelines that provide a public health model for HIV disease management in resource-poor settings. Compared to U.S guidelines that stress an individually tailored approach to HIV therapy including protease inhibitors and sophisticated laboratory tests, the draft guidelines emphasize the simplicity, economy, and relative safety of nonprotease regimens. They also encourage syndromic management of HIV, which emphasizes careful tracking of physical symptoms while limiting lab testing to the basics.

The WHO's bare-bones model stresses potent initial treatment regimens that do not require substantial improvements in health infrastructure. It is designed primarily for the senior policymakers and treatment advisory boards that are establishing developing countries' AIDS treatment programs. It is sure to help frontline doctors as well.

The guidelines reflect sobering lessons learned from a decade of using protease inhibitors in richer countries. Today, serious side effects and drug resistance are linked to long-term use of HIV drug cocktails. Some patients no longer have any effective treatment options available while others have put off commencing treatment in the first place. The most recent versions of the U.S. government's treatment guidelines reflect this trend. They no longer advocate a "hit early, hit hard" approach to HIV treatment. Rather, they urge physicians and patients to carefully weigh the risks and benefits of therapy. The U.S. guidelines also play up the critical role of patient education and emotional support to help individuals adhere to a taxing lifetime regimen. These issues pose even greater challenges in the developing world.

The WHO's new guidelines reflect a collective awareness that economics, not science, drive health policy in developing countries. At the same time, the guideline drafters stress that their proposed guidelines should be read as a rough map for therapy, not a blueprint. There is considerable debate among the experts over many topics in AIDS care. One of the strengths of the WHO document is that it pinpoints some of the minefields facing clinicians and patients. It also draws attention to steps that could be taken to fill in gaps in our knowledge.

Some critics have questioned the ethical issues underlying advocacy of a different therapeutic standard for poorer vs. richer countries. The guideline's authors defend their approach, noting that prior clinical guidelines for HIV therapy were developed for use in high- and middle-income countries. The guidelines are not meant to be a substitute for the necessary national AIDS treatment programs, but "are meant to facilitate the dramatic scale-up that is needed in countries with limited infrastructure and significant resource limitations…."

"I was part of the committee that came up with the guidelines," stated Dr. Mark Wainberg, an HIV specialist at McGill University and former president of the International AIDS Society. "I don't think they are perfect, but I doubt whether any similarly constituted group would improve significantly on the recommendations. In spite of my bias, I think that the two NRTIs plus an NNRTI concept is ethical as well as practical. Protease inhibitors were considered less reliable because of potentially non-monitored toxicities in resource-poor settings."

Dr. Sam Narasapa of Chennai, India agreed: "I have no doubt that the [nonprotease] regimen suggested will work. We need to be bold and ensure that this therapy will benefit individual patients. This will contribute to the reduction in viral burden transmission in the community. We must remember that these are guidelines and it is left to the individual physician as to how he will treat the patients. Training and hands-on experience is essential."

Principles for Minimalist Therapy

The main topics covered in the WHO guidelines concern the initiation of anti-HIV therapy: when to start, what drugs to use, when to switch, how to monitor treatment, problems of toxicity and resistance. The guidelines also consider specific treatment issues concerning women (including pregnant women), children, drug users and other special groups. These also cover potency, dosing, drug interactions, managing HIV-TB coinfection, and the difficulties of distinguishing symptoms of HIV drug failure from immune restoration syndrome.

The guidelines limit anti-HIV treatment to patients who are seriously ill, using the WHO staging criteria for HIV disease. Treatment is advised for individuals with WHO Stage IV disease (clinical AIDS), those with WHO Stage I, II and III HIV disease and CD4 T-cell counts below 200, and those with WHO Stage II and III HIV disease and a total lymphocyte count (TLC) below 1200. The recommended first- and second-line combination therapy contains a dual nucleoside analog regimen of AZT/3TC combined with efavirenz, nevirapine or abacavir. Acceptable substitutions include d4T/3TC, d4T/ddI and AZT/ddI for the dual nucleoside analog component. The guidelines duly note that cross-resistance to nucleoside analogs can develop, making adherence to dosing schedules critical. Some of the nucleoside analogs' side effects, such as lactic acidosis and liver enlargement, are of particular concern to pregnant women and children.

The guidelines promote a tiered scale for laboratory testing, starting with "absolute minimum tests" that include an HIV antibody test and a blood test for hemoglobin and hematocrit level. "Basic" testing includes a white blood cell count and differential that can pick up common treatment side effects such as low neutrophil count as well as providing a total lymphocyte count (TLC). In studies to date, the WHO working group notes that TLC correlates poorly with CD4 levels, but provides a good marker for prognosis and survival when used with WHO clinical disease staging criteria. Other "basic" tests include blood sugar, liver and kidney function, and pregnancy tests. "Desirable" tests include bilirubin, amylase and serum lipids. These are particularly useful for monitoring drug toxicities as well. CD4 T-cell tests are also "desirable," but viral load testing is merely optional.

Drug resistance tests do not make the list at all, being too costly. But resistance testing for sentinel purposes is needed to identify resistant viral strains in a given population. The WHO is now setting up a Global HIV Drug Resistance Network to assist member states in this task. To help individuals adhere, the guidelines recommend a low-cost formula used in the U.S.: patient education, continued counseling and when possible, involvement and support by the family or community. They also suggest a strategy of Directly Observed Therapy (DOT) for HIV therapy borrowed from TB management.

What about the older and cheaper dual nucleoside analog regimens? Avoid them if possible, say the WHO experts. Such regimens are less potent and lead to resistance. But what if there's no money for three drugs? Case studies show patients can still benefit from suboptimal therapy. Ethically, many doctors choose to treat sick or dying patients with two drugs and grapple with resistance later. The WHO draft guidelines support this choice. If a two-drug regimen appears to be working, they suggest keeping a patient on the regimen and switching over to three drugs when possible. "The concession regarding two drugs reflects eality and represents a dilemma since individuals have a right to benefit from such therapy, notwithstanding the problem of drug resistance," acknowledged Wainberg.

Real World Complications

How useful are these guidelines for doctors and patients? What is good in theory can be hard in practice. The guidelines pay little attention to food and nutrition, but doctors in the field say this is a critical aspect of managing HIV. STD screening and treatment and prevention of opportunistic infection are also given short shrift. There is passing mention of complementary herbal therapies and traditional medicine used in different countries.

Nonmedical and social issues also fall outside the scope of the guidelines that impact on access to care. Left unaddressed, for example, is the issue of public stigma that makes people reluctant to get tested for HIV and reluctant to seek care until they are quite sick. That includes discrimination by health professionals who fear exposure to the virus.

In the developing world, HIV is linked to poverty and rides on the coattails of endemic diseases like TB, malaria, and parasitic or fungal infections. Treating HIV there requires managing these multiple infections. The draft guidelines note that coinfections like TB promote HIV disease progression and vice versa. Also, HIV drugs interact negatively with those for TB and other diseases. They suggest treating active TB cases first, to avoid stressing the liver and causing drug interactions. But that is not possible in persons with advanced HIV disease.

Immune restoration syndrome poses another challenge. Some patients have experienced serious flare-ups of hepatitis and other diseases after initiation of anti-HIV therapy. Such acute illness represents an intense inflammatory reaction to preexisting indolent infections. Without comprehensive lab testing, it is difficult to determine whether these symptoms results from treatment success and immune recovery, treatment failure and HIV disease progression, or drug-induced toxicities. This issue is likely to be a particular problem in developing countries, where hepatitis is rampant.

Given their cheap cost and simplicity, there is no question that nonprotease regimens make sense as universal therapy. But in the longer term, there are potential serious consequences. The long-term impact of specific drug toxicities on children and women of childbearing age is critical. So is future resistance to HIV. In many developing countries, chronic and often improper use of drugs has led to multidrug-resistant strains of TB and malaria. What are the odds of doctors doing better with HIV therapy?

India Improvises

India provides a reality check and an early warning for the experts. The HIV epidemic there affects four to 12 million people. Heterosexual sex is the primary route of transmission. Around 10% of HIV-positive patients are so sick they need treatment now, but only a few thousand are receiving anti-HIV drugs. There is little public education about AIDS or HIV and their treatment, but there is a lot of stigma and discrimination, even by health professionals. Like many countries, India has excellent doctors, nurses and midwives, but not enough of them in rural areas where HIV has spread. Around 500 physicians are treating HIV in India, mostly in major cities. The majority are dermatologists who have become de facto HIV specialists because they see STD patients.

Dr. Shashank Joshi is a U.S.-trained infectious disease specialist in Bombay who has treated almost 500 HIV patients over nearly five years. He treats wealthy private patients and very poor patients at a public hospital. The rich ones get all the perks available in the U.S., including protease inhibitors and viral load testing. The poor make do with the nonprotease regimens and syndromic management outlined in the WHO guidelines. So far, he has had remarkable success attacking HIV in both settings, but Joshi says that he is the exception rather than the rule.

"I think the overall health system in India is very bad," Joshi remarked. "The vast majority of doctors here practice bread and butter medicine. Very few are trained abroad as ID doctors. They are just handling patients as they come in with HIV disease and doing symptomatic treatment."

Up to now, he said, HIV therapy has been erratic, unsupervised and often suboptimal. "That's medicine in India. Everybody and anybody can prescribe antiretroviral drugs in India. So they make their own regimens, for their own convenience and their own pockets. It doesn't necessarily translate into quality of care. God save the patients who are on all these crazy protocols."

Joshi often sees patients referred by other doctors. "Most of their prescriptions are not up to the mark," he remarked about his colleagues. "They don't know what to combine with what. I can show you prescriptions where it's AZT plus d4T." (As the WHO guidelines point out, AZT and d4T are antagonistic with each other and should never be taken concurrently.)

Joshi feels that Indian-based treatment guidelines coupled with continued medical education of physicians are the way forward. "But that could take some time – and money," he acknowledged, "We don't have much of either."

He is also concerned about what he calls "over-reliance" on nonprotease regimens in populations who suffer from liver damage due to chronic use of drugs to treat TB or parasites. "In Indians, liver toxicity is going to be a hundred-fold more because they are exposed to anti-TB drugs," he predicted. Aside from liver problems, Joshi has also seen rashes from nevirapine and abacavir and neuropathy with some regimens.

"All the nukes are toxic, all the NNRTIs are toxic," declared Joshi. "It's done for convenience, compliance, cost – two pills twice a day. People are not prescribing PIs because they are inconvenient to take, they are large and they are bitter. But that is not always the right thing to do. There will be cases when all these non-PI regimens are defeated by drug resistance, and you have to use only salvage regimens."

But Joshi certainly does not give the protease inhibitors an unqualified endorsement. He published his first report on treatment-related diabetes and lipodystrophy in patients using protease inhibitors last November. "Among my elite cohort of 300 patients, there is a high incidence of lipodystrophy," he noted.

One patient suffers from avascular necrosis resulting in deterioration of his hip bone. "We are going to see that," Joshi said. "There is no way to prevent anything." He has put a small number of patients on experimental cyclical treatment interruptions, mainly one month on therapy and one month off, to reduce toxicities and buy them time. "I am extremely happy with my results," Joshi remarked. "The CD4 curve is either flat or up. The viral load is almost undetectable, but in a couple of cases we do get rebounds. In early disease," he argued, "I believe it should be standard of care. In later or chronic disease, I am not so sure. Our observations are very preliminary."

Other Indian doctors share Joshi's improvising ways. Indian HIV patients often have very low baseline hemoglobin levels or anemia due to chronic malnutrition. That rules out AZT for first-line regimens because this drug itself causes anemia. "I don't use much AZT because most of my patients have hemoglobins under 10 or 12 grams and AZT is a killer for them," stated Dr. Ishwar Gilada, a dermatologist turned HIV specialist with a thriving practice in Bombay.

Gilada treats most of his patients with generic nonprotease regimens and has not seen many problems. Because his patients are often underweight, he deliberately lowers drug doses, using a dose-per-kilogram scale borrowed from pediatric medicine. "This works well for my patients and reduces toxicities," he said. "Many of our doctors are learning to do this." Such steps deviate from the WHO guidelines and pose the risk that HIV will acquire drug resistance from exposure to suboptimal therapy.

In Indian patients, alcoholism is another common factor that increases the risk of liver toxicity. "Liver monitoring is the most important test," noted Gilada. His patients have their liver function monitored every two to three months. "If it's OK, we increase the follow-up time." Luckily, many can afford CD4 and viral load tests, so monitoring is easier. So far, Gilada said that 5% of his patients have had typical minor skin problems caused by nonprotease drugs, and 1% to 2% have had serious problems.

In Chennai, Dr. Narasapa has seen one patient with nevirapine-induced hepatitis, and hypersensitivity reactions in three women taking nevirapine-containing nonprotease regimens. Narasapa worries about the potential consequences of nonprotease regimens. He remarked, "The only way to minimize long-term effects is to see that counseling is given more than once. And the training of physicians is important."

Managing coinfections remains the biggest daily challenge for most doctors, said Joshi. "Ninety percent of doctors here start people on anti-TB drugs without really diagnosing, based on weight and other symptoms. That is why India has the highest rate of multidrug resistant TB. INH [isoniazid] resistance is 40%, rifampin resistance is over 30%, and almost every second-line drug is resistant." These statistics do not bode well for syndromic management of HIV, he feels. Joshi concluded, "We need to be prepared to manage resistant HIV."

Social and religious issues present other barriers to treating HIV, making some regimens and side effects more acceptable than others. The NNRTI efavirenz is a problem. "In India whenever we give efavirenz, we get tremendous sweating, fully wet, as if they've taken a bath. And that is socially unacceptable in India," reported Joshi. His wealthier patients quickly abandon the drug. "They will say to hell with it, even if I get a pot belly, even if I get diabetes, I don't care, I will take a PI."

Diet is also a big issue in India. The typical Indian diet is oily, which makes it hard for patients to use PI-based regimens. Some people regularly fast, which affects adherence and absorption of drugs. "My patients don't want to compromise on their eating habits," Joshi shrugged. "These are the realities we have to deal with every day."

Like many Indian doctors, Joshi routinely uses Indian ayurvedic or herbal compounds, alongside standard Western medications. But he is aware that little is known of potential drug-herb interactions. "What I'm concentrating on are non-drug options to increase CD4 and decrease viral load," he explained. "In my patients who were failing salvage therapy, I began trying other things like deworming agents. The viral load comes down. My whole aim is to develop cheap, cost-effective protocols for the Indian environment."

Summing up the task at hand, Gilada said, "We have to be creative and watchful, keeping in mind that the well-being of our patients comes first. We will make mistakes just as doctors in the U.S. have made them. But we are learning as we go forward."

This article has been reprinted from the Treatment Directory at amfAR.org

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