HIV, HBV and HCV in Europe: Border Crossings and Buried Bombs

• Introduction
• Border Crossings
• Buried Bombs
• References and Notes

Introduction

Why did tiny Holland -- tiny, resource-poor Holland -- become a world power in the 17th century? How could a brand-new nation with only 200,000 citizens outmuscle rivalrous world powers to dominate the trade wars while fostering peace, prosperity, and a cultural efflorescence at home?

Tolerance is one answer, proposed Joep MA Lange (Academic Medical Center, Amsterdam) in opening the International Association of Physicians in AIDS Care (IAPAC) European Sessions 2005. The plucky Dutch not only welcomed Sephardic Jews driven from Spain, they declined to kill Catholics and homosexuals, gave women unheard-of license, and revered children.¹

Not a bad recipe for success, it seems, but a rare one. Today many Dutch and more than a few of their European neighbors "take the opposite view" on immigrants, Lange noted. "But of course they have no sense of history."

HIV has only a short history, but one already rife with anomie as parents, teachers, soldiers, and doctors die; as farms fail; workers quit; and barely nubile girls get HIV and pass it on. This tragedy may play to the last bloody act only in Africa -- unless India or Russia, for example, teeters past the brink. But the sub-Saharan epidemic, and those in the Caribbean and beyond, already spark incendiary inroads through Western Europe and any other place AIDS-harried migrants can reach, legally or not.

In three insightful talks, IAPAC Sessions limned the imprint of this nomadic retrovirus on a Europe that never wholly defused its own epidemic. The balance of this two-day parlay also evinced a sure sense of history, invoking what's known to envision what's not about antiretroviral strategies, antiretroviral side effects, and hepatitis virus coinfection.

Border Crossings

If you want to place blame for Europe's cyclic struggle with contagion, blame civilization, contended Mark Nelson (Chelsea and Westminster Hospital, London). In antediluvian days our footloose forebears -- living in small tribes that seldom crossed paths -- worried about hunger and scavenging hyenas, but not about infectious disease. That changed for good, but perhaps for worse, when the sapient species set up cities, kept pets, bred animals, and built armies.

When 200,000 people holed up in Athens to avoid Sparta's sword in 430 BCE, Nelson noted, the plague holed up too and killed a third of them. Roman legions returning from Syria in 166 CE brought buboes and pox back with them, slaughtering four million or more. Four years later "barbarian boils" came to China with northern marauders. Many died and the Han dynasty crumbled. Talk about anomie.

Columbus slew thousands, not with Spanish steel, but with flu, measles, smallpox, tuberculosis (TB), and gonorrhea. Perhaps not coincidentally, syphilis showed up in Europe at the same time, touching off fierce rounds of epidemiologic finger pointing. The French called it the Neapolitan disease, the Neapolitans called it the German disease, the Germans called it the French disease, the Poles called it the German disease. And so on.

Migration Mediates Infection

If everyone stayed put in their place of birth, nascent epidemics -- confined to their epicenters -- would stay put too. But Homo has long been a migratory beast, probably since attaining erectus status. Except for the few who stayed forever in East Africa, we are all migrants -- a point worth considering when xenophobic fustian tempts.

Perhaps 185 million migrants now roam the world, Nelson reported, 60 to 65 million seeking work, another 60 million following them, and another 15 million fleeing persecutors. One in 35 people -- 3% of the globe's populace -- can be called an international migrant. Nearly half are women. In Europe alone, added session chair Alberto Matteelli (Spedali Civili University Hospital, Brescia, Italy), 20 million people -- 5.2% of the population -- live outside their country of citizenship. Nearly one in 10 residents of Austria, Belgium, and Germany are immigrants (Table 1).

Migrants from countries with runaway HIV epidemics account for two thirds of heterosexually acquired HIV infections in Western Europe.² In 2002, about three quarters of Britain's heterosexually acquired infections involved people from Africa, and in Germany most new HIV diagnoses are made in people born elsewhere. 2 More than 80% of Sweden's HIV infections happened outside Sweden, and nearly three quarters of Belgium's heterosexually acquired HIV infections involve migrants.²

The disproportionate HIV burden among migrants in Europe shows no sign of stabilizing. Today's 185 million international migrants will swell to 230 million by 2050, Nelson said. And research hints that HIV will not stay circumscribed in migrants' ethnic circles. Migrant men in The Netherlands, for example, reported that nearly half of their sexual liaisons involved partners of other ethnicities.³

If migrants from the epidemic's vortex do not bring HIV with them, they run a high risk of picking up the retrovirus in their new home or of getting a late diagnosis or poor treatment. Nelson and Matteelli spelled out several factors behind these trends:

• Vulnerability to sexual exploitation and harassment

• High HIV risk when visiting their native country

• Poor access to health care, including prevention services, counseling, and testing

• Work in an isolated environment (separated from families, communities, norms)

• Lack of legal protection

Late HIV diagnosis threatens not only the infected person, but also that person's sexual partners.

The risk of picking up HIV during visits home may be particularly acute for immigrants socially isolated in their adopted country. Among Africans living in London, Matteelli noted, 40% of men and 20% of women found a new sex partner when traveling abroad.⁴ Still unpublished research found that 47% of men and 11% of women who visit friends and relatives in Suriname or the Antilles after settling in Amsterdam meet a new sexual mate on their trip. HIV gene mapping shows that half of the HIV-infected from these lands now living in The Netherlands got infected in their homeland.⁵

HIV is hardly the only infectious disease immigrants bring to Europe or get once they settle there. In England and Wales, Nelson reported, migrants accounted for 73.1% of TB cases in 1999. That proportion inched inexorably upward to 79.9% in 2000, 80.8% in 2001, 90.7% in 2002, and 90.9% in 2003. Foreign-born residents make up more than half of the TB case load in six Western European countries -- Britain, Denmark, Luxembourg, The Netherlands, Norway, and Sweden -- and about one third in Belgium, France, and Germany.

All these trends add up to one safe wager, according to the World Health Organization (WHO): The number of people needing antiretrovirals in Europe will climb sharply over the next five years (Table 2).

Caring for HIV-Infected Migrants

Migration surely does not completely explain recrudescent HIV incidence in Western Europe. But some see immigrants as an easy target of nationwide prevention tactics. Close the tap and cut the flow, this paralogism purports.

But it's not that simple, said Nelson and others at IAPAC Sessions. First, predeparture HIV testing wafts an unethical fetor when done without consent, confidentiality, or counseling. Second, it doesn't work. People who have HIV or think they might will not roll up their sleeve for an HIV test when they want to get into another country. They'll try to get there illegally. If they succeed and if they have HIV, they will spread the virus.

Instead Nelson proposed strategies for educating migrant populations about sexually transmitted diseases and for managing HIV infection in those already infected. Education should have five goals, he suggested:

• Promoting HIV testing

• Offering sex education

• Promoting sexual health

• Destigmatizing HIV disease

• Destigmatizing routes of HIV infection

Nelson thinks family-focused clinics stand the best chance of stopping HIV among immigrants for three reasons: Families have complex health needs including pediatric, adult, and pregnancy concerns. Family health problems go well beyond the skills of any one health worker. Families comprise discrete units that lend themselves to an all-embracing health care approach.

Besides offering the talents of many specialists, family clinics have some practical pluses for HIV-infected immigrants and their kin, including manageable appointments on the same day, and fewer appointments with less travel time and expense. The ideal HIV family clinic, Nelson proposed, would offer the following amenities:

• Regular meetings with a multidisciplinary team

• Weekly clinics with a pediatrician and adult disease specialist

• Shared clinics in the same room (although that may be impossible)

• All blood work done before the family visit

• Child space in the clinic

Nelson urged colleagues treating migrant populations to think carefully about the antiretrovirals they prescribe. Too often, he cautioned, clinics adopt a standard first regimen then prescribe it to all comers. At London's Chelsea and Westminster Hospital, for example, efavirenz (EFV) plus tenofovir (TDF) and emtricitabine (FTC) emerged as the preferred blend. But is it the right regimen for black Africans?

Africans often carry mutations in CYP2B, the enzyme that drives EFV metabolism. Those genetic wrinkles can boost EFV levels and spur early, intolerable side effects. Renal worries lead the short list of TDF toxicities, and Africans generally suffer more kidney disease than other groups. Emtricitabine has also proved a highly tolerable drug. But one of its side effects -- hyperpigmentation -- can leave blacks with an unwanted badge of HIV infection.

Plugging Holland's HIV Dike

Frank de Wolf (HIV Monitoring Foundation, Amsterdam) has a solution to uncontrolled immigration of people with HIV that is more sublime and, on its face, simpler than Nelson's family clinic plan: Treat everyone who needs treatment before they leave home.

Though hardly cant, de Wolf's modest proposal will take decades to effect, and he realizes that as much as anyone. But HIV can't be kept out of Europe, he noted, with the handy finger-in-dike feat of Hans Brinker, the Dutch boy of (American) legend who saved Holland's sea-menaced polders by plugging a leak with a plump digit. North Sea swells would have whelmed Brinker -- and Holland -- if the bustling Dutch had not ringed lowlands with high dams in the first place. Years of planning and hardheaded mud molding kept Holland dry, not an expedient finger. It will take as much work to stop HIV.

And of course defusing immigration by treating everyone in their native land will do nothing about migrants already settled in other countries. But The Netherlands has long since figured out what to do about them: Treat everyone who needs treatment after they migrate.

De Wolf figures about 80% of people who need antiretrovirals in The Netherlands -- including immigrants -- get antiretrovirals. As a result HIV-related morbidity skidded from 15.4 cases per 100 person-years in 1996 to 1.43 per 100 person-years in 2004. Over the same years mortality among people with HIV plunged from 4.62 to 1.55 deaths per 100 person-years. A small mortality spurt marred this record in 2005, de Wolf noted, but so far this trickle lacks statistical significance.

These rates come from a cohort of 8,439 people -- 957 of them with AIDS -- who deluged statisticians with 40,000 years of follow-up data. About 80% of treated people reached a viral load below 500 copies/mL in their first 48 weeks of therapy, and about 75% of them started with a load topping 100,000 copies/mL. Among people whose RNA tally exceeds 500 copies/mL, the average load lies 1.5 log copies/mL below pretreatment values after five years of follow-up. A lower nationwide viral load, de Wolf suggested, will slow the epidemic by cutting transmission risk.

As Netherlandish viral loads stay below sea level, CD4 counts continue to surge. Most CD4 subgroups in de Wolf's cohort kept adding T cells through 240 weeks of follow-up. Only people who began treatment with more than 600 cells/mm³ hit a CD4 high-water mark -- at a normal 800 cells/mm³.

Despite the clear impact of antiretrovirals, de Wolf warned, several factors could spur a rising tide of new HIV cases in The Netherlands:

• A growing contingent of relatively healthy people with HIV means a wider pool of potentially transmitted virus.

• As soon as HIV-infected people start feeling well, they start having sex -- sometimes risky sex.

• A spurt in sexually transmitted diseases in The Netherlands reflects a national surge in condom-free intercourse.

• HIV will continue to arrive from abroad (Table 3).

Indeed The Netherlands began to see a rebound in HIV incidence after 2000. From 1996 through 2000, incidence had dropped steadily.

Today women and girls born outside The Netherlands account for 53.3% of the country's female HIV cases. In contrast, 65.7% of men and boys with HIV are Dutch. Among immigrants with HIV, women and girls outnumber men and boys in groups from sub-Saharan Africa, Ghana, and Thailand (Table 4). Males far outnumber females in HIV-infected cohorts from the Antilles and Suriname.

HIV diagnoses per year climbed precipitously from 1996 through 2005 for sub-Saharan Africans and Ethiopians living in The Netherlands. Diagnosis rates also rose, though less dramatically, among people from the Antilles, Ghana, Latin America, Suriname, and Thailand.

Immigrant groups get treated for HIV in The Netherlands as consistently as the native Dutch, de Wolf reported, and they respond as well on most measures. The exceptions involve slower CD4 gains among people from the Antilles, sub-Saharan Africa, and Suriname. Differences in adherence to therapy may contribute to those tardy responses, but that's a guess because de Wolf does not have adherence data on the cohort.

Co-Chair Joep Lange observed that some African populations have lower CD4 counts than Europeans regardless of HIV infection. Without more complete baseline numbers, he suggested, cross-ethnic CD4 gain comparisons remain tenuous.

Virologic responses in immigrant groups mirror responses in European natives: 65% to 85% of immigrants have RNA readings under 500 copies/mL 20 to 40 months after starting antiretrovirals. And non-Dutch groups stick with their first regimen as long as Dutch natives. But people from the Antilles, Ghana, and Suriname have faster rebounds than the Dutch.

Antiretroviral-treated immigrants do not differ from the Dutch in overall survival or, in an analysis adjusted for CD4 count, in AIDS-free survival.

Perhaps the most astonishing statistic from de Wolf's portfolio is the proportion of immigrants still free of AIDS symptoms when they get diagnosed with HIV: 70% to 80%. Those rates do not differ from the proportion of symptom-free HIV diagnoses among the Dutch.

British statisticians tell a different story, Nelson noted: 90% of immigrants in the United Kingdom have HIV symptoms when they get their first positive test. Indeed, most of them get tested because of their symptoms. Why the stark difference? Lange thinks two factors may explain early HIV diagnoses among immigrants in The Netherlands: Many groups have strong social networks that foster HIV education programs. And anyone coming to The Netherlands knows an HIV diagnosis and low CD4 count entitle them to free treatment.

Immigrants With HIV in Italy

Before 1994, native Italians accounted for more than 95% of HIV diagnoses in Italy and immigrants for fewer than 5%. The ratio has narrowed steadily ever since, Matteelli reported. According to the Italian National AIDS Registry, nonnatives first made up more than 10% of HIV diagnoses in 1998 and 1999. By 2004 they accounted for nearly 20%.

In Modena, a city southwest of Venice, 2.3% of new HIV diagnoses involved immigrants in 1985. That rate rocketed to 32.1% in 2000. In Brescia, Matteelli's base in Lombardy, the Institute of Infectious and Tropical Diseases attributed 5% of incident HIV cases to foreign-born people in 1986 and 21% to nonnatives in 2003. At Italian sexually transmitted disease clinics, HIV prevalence drifted downward from about 7% in 1991 to 4% in 1996. From that point through 1999 it quadrupled.

A 2005 study of 465 illegal immigrants in Brescia confirmed active and often omniform sex lives. Among the 70% who reported sexual intercourse within the past year, 52% had a steady partner, 48% entertained casual partners, and 7% paid partners. In those three groups, 93% who paid for sex regularly used condoms. But only 51% with casual partners and 21% with regular partners routinely wore condoms.

As in Britain a whopping majority of HIV-diagnosed immigrants in Brescia already have symptoms when their test comes back positive (Table 5). In comparison only about one third of Italians have symptoms when diagnosed. A comparison of 1,904 native Italians and 215 immigrants found that 27.7% of Italians had a CD4 count under 200 cells/mm³ at diagnosis compared with 36.3% of immigrants. Late diagnosis, Matteelli reminded colleagues, qualifies as a transmission "risk behavior."

Once HIV-infected immigrants in Brescia start antiretrovirals, adherence can be iffy. Matteelli reported that more than half of the immigrant group interrupted therapy within 12 months of starting. Female gender, older age, and African origin boosted the risk of suspended therapy. Matteelli believes health workers caring for immigrants must work harder to explain the need for treatment, its impact on infection, and its potential side effects. At the same time they should discourage behavior that favors HIV transmission.

Matteelli echoed Lange's concern over an increasingly xenophobic mindset in Europe and elsewhere. He closed his talk with a comment made by Judith Kumin, the United Nations High Commissioner for Refugees regional representative in Belgium.

"Politicians across the globe have won elections by fueling nationalistic and xenophobic sentiments," Kumin said at the 2005 Caritas Europa 4th Migration Forum, "blaming a variety of ills -- insecurity, unemployment, housing shortages, overcrowded classrooms -- on immigrants, including refugees and asylum seekers." As with syphilis, of course, many blame foreigners for HIV.

Buried Bombs

Sessions organizers had to do some fast schedule shuffling on the meeting's first day because three speakers got stuck on their way to Amsterdam. The sticking point was a 500-pound World War II bomb discovered during digs at Schiphol Airport, which -- along with a painterly fog -- closed runways and snarled air traffic across the continent. The Royal Air Force dropped this particular payload, missing Germany by a wide mark. By the time authorities lugged away the widowmaker, airlines had cancelled two speakers' flights and delayed a third by half a day.

Bombs buried at international airports make headlines while making hash of schedules. But within 24 hours CNN's news cycle disgorges such fortuities and cybervillagers sit back to await the next tsunami, earthquake, or war. Something with at least a week's worth of round-the-clock video feeds.

Bombs latent in cryptic pathogens (and in their treatment) get less media play if they are not new (SARS), sanguinary (Ebola), or vaguely apocalyptic (bird flu). Truly apocalyptic infections -- AIDS, TB, malaria -- rarely breach the news cycle these days unless they seemingly threaten media capitals ("Super AIDS Bug in New York!"), perhaps because the yearly death of three million noncelebrities fast becomes tired copy, perhaps because the visuals lack drama. (Soweto clinics? Lesotho huts? Delhi hovels?)

Yet epidemic HIV surely hides countless buried bombs. How bad will it get in China, Papua New Guinea, or Russia? How will cross-clade superinfection⁶ and recombination prod viral evolution? And -- more immediately, if less spectacularly -- what still-covert side effects lie in wait for the many fated to gulp antiretrovirals for 20, 30, 40 years? Though prescient experts such as Charles Flexner (Johns Hopkins University, Baltimore) registered early fears over the toxic potential of drugs studied fast in small groups, none could foresee the noxious fat fluxes attendant on therapy, and no one supposed heart attacks would kill middle-aged men with double-digit viral loads.

Opening the IAPAC Sessions review of antiretroviral side effects, Peter Reiss (Academic Medical Center, Amsterdam) warned that more toxic surprises may lurk "below the surface" surveyed in HIV's ample literature. Why do people with well-controlled replication complain of fatigue, flaccid sex drives, and borborygmic bowels? Probably not because they're whiners. Something must be going on.

Side effects session chair Nathan Clumeck (St. Pierre University Hospital, Brussels) reminded colleagues that it took years to pin down the toxic threats of stavudine (d4T). Even after several groups sounded the alarm in 1999, reasonable exculpatory arguments persisted more than a few months. In retrospect one easily forgets that d4T/lamivudine (3TC) became the anointed backbone because it seemed both potent and safe. That transient blindness fostered generic blends of the two nucleoside reverse transcriptase inhibitors (NRTIs) that now abound in poor countries struggling to slow HIV.

Is there a rich-poor double standard in d4T use, Clumeck asked Reiss. Yes, Reiss answered, though a choice between d4T/3TC regimens and no regimen remains an easy pick. Clinicians in AIDS-ridden countries do see lipoatrophy in people taking d4T, he added. Whether stigmatizing fat loss proves as frequent or bad there as it became in Europe -- or worse -- no one knows.

When Clumeck asked if zidovudine (AZT) should be "blacklisted" for its peripheral fat-depleting penchant, Reiss proposed that clinicians "can't afford the luxury" of avoiding AZT. Although AZT thins subcutaneous fat more slowly than d4T, Reiss believes it does so inexorably. Yet research on AZT-induced lipoatrophy remains inconsistent. Analysis of the US Nutrition for Healthy Living Cohort correlated AZT with a 4.9% loss of arm and leg fat -- and 10.8% loss of trunk fat -- for every year of use.⁷ In this cohort, d4T looked blameless. But AIDS Clinical Trials Group (ACTG) investigators charted a small 64-week limb fat gain in people randomized to AZT/3TC (+4%) rather than didanosine (ddI)/d4T (-16.8%) in ACTG 384.⁸

Lange wondered whether only d4T and AZT, the thymidine analogs, deserve all the blame for lipoatrophy. Zalcitabine (ddC), he reminded colleagues, fell from favor because of its bleak toxicity record. Lange added that both ddC and ddI ranked poorly in early mitochondrial toxicity studies. But more recent work focused on fat cells found significantly less mitochondrial DNA depletion with abacavir (ABC) and nonthymidine analogs than with d4T or AZT.⁹

What other bombs lie buried? Lange noted that the general lack of systemic toxicities with enfuvirtide (ENF) does not mean such side effects will not crop up in people who take the injectable fusion inhibitor long enough. And despite TDF's still glistening lipoatrophy record, Nelson warned that could change with longer use. What about long-term kidney toxicity with TDF? A year and a half of follow-up in the Johns Hopkins cohort did show significantly worse creatinine clearance with TDF than with other reverse transcriptase inhibitors,¹⁰ Nelson added. But long-term follow-up in the TDF-versus-d4T trial¹¹ and in Nelson's Chelsea and Westminster cohort¹² did not flush out a latent risk of kidney toxicity with TDF.

HIV, Lipids and MI Risk

Reiss assured IAPAC Sessions attendees that for people taking antiretrovirals "myocardial infarction [MI] is not a major health crisis -- yet." Although the latest results from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study confirm a nearly linear jump in MI risk with each added year of antiretroviral therapy,¹³ "in absolute terms" the MI threat "remains a relatively minor problem" that does not add up to an antitherapeutic argument.

So should one bother taming unruly lipids? Yes, Reiss argued. The D:A:D study also found that out-of-line lipids modulate antiretroviral therapy's impact on MI risk.¹³ A statistical model reckoning the cumulative yearly impact of therapy showed that each extra year of treatment boosted MI risk 17% (relative rate [RR] 1.17, 95% confidence interval [CI] 1.11 to 1.24). But in a model factoring in lipids and other variables, each extra year of therapy raised the risk 10% (RR 1.10, 95% CI 1.01 to 1.19, P = 0.03). So high lipids must play some role in people with HIV. In the same analysis each log₂ mmol/L higher triglyceride reading jacked the MI risk 64% (RR 1.64, 95% CI 0.98 to 2.74, P = 0.06), and each mmol/L higher total cholesterol value swelled the risk 15% (RR 1.15, 95% CI 1.06 to 1.25, P = 0.001).

At the same time clinicians can't ignore other tractable MI risk factors that abound in the D:A:D cohort and in most groups taking antiretrovirals -- smoking (52% of the D:A:D cohort), hypertension (8.5%), body mass index above 30 kg/m² (3.5%), and diabetes (2.5%). Smoking drove up MI risk substantially more than each year of antiretrovirals in a model including both variables.

Stop the PI or Start a Lipid Lowerer?

What's the best way to rein in baneful lipids? Until a few months ago, Reiss preferred switching people taking a protease inhibitor (PI) to a nonnucleoside reverse transcriptase inhibitor (NNRTI). But he started questioning that stance when Italian clinicians reported that mean total cholesterol dropped more over one year in people randomized to take pravastatin (-46%) or bezafibrate (-38%) than in those switched to nevirapine (NVP) (-27%) or EFV (-10%).¹⁴ People assigned to a lipid-lowerer also did better than the switch groups in easing low-density lipoprotein (LDL) cholesterol and triglycerides. Differences between the antilipid and switch groups were statistically significant.

Reiss noted, though, that these researchers signed up only about 30 people per treatment arm, so confirming work would be welcome. And on the other side of the equation, some evidence suggests lipid busters lack punch in people with HIV. In a 16-week trial that randomized people with triglycerides at or above 3 mmol/L to diet plus gemfibrozil or diet alone, gemfibrozil pushed triglycerides below 2 mmol/L in only one of 17 men.¹⁵ Gemfibrozil did not alter cholesterol levels or insulin resistance. And a 48-week ACTG study found that pravastatin and fenofibrate -- first alone, then together -- rarely brought bollixed lipids back to National Cholesterol Education Program (NCEP) targets.¹⁶ But the combined drugs proved tolerable and did shove lipid readings in the right direction.

Trading a PI for an NNRTI -- if it does not threaten viral control -- has one clear advantage over prescribing antilipidemics: It often simplifies therapy rather than complicating it. And at this point few doubt that PIs drive lipids askew more than other antiretrovirals. Further D:A:D data show consistently higher triglycerides, LDL cholesterol, and total-to-high-density lipoprotein (HDL) cholesterol ratio in people taking one or two PIs than in treatment-naive people or those taking two NRTIs plus an NNRTI.¹⁷ And two PIs proved consistently worse than one PI. A similar analysis by Dutch and D:A:D researchers documented worse triglyceride, total cholesterol, and LDL cholesterol profiles in people taking a first-line PI than in those taking a first-line NNRTI.¹⁸

But Reiss cautioned that lipid differences between people starting treatment with PIs versus NNRTIs are subtle. In a Swiss cohort of 1,065 people primarily starting lopinavir (LPV)/ritonavir (RTV), indinavir (IDV)/RTV, nelfinavir (NFV), or EFV, non-HDL cholesterol rose regardless of regimen.¹⁹ Triglycerides tended to climb with PIs (especially RTV-boosted PIs), to drop slightly with NVP, and to rise slightly with EFV. High-density lipoprotein cholesterol improved with NNRTI regimens. Among the most-prescribed PIs, NFV stirred lipids less than LPV/RTV or IDV/RTV.

The lipid lines that may separate EFV from NVP can be blurry, but the D:A:D cohort analysis¹⁷ echoes the Swiss HIV Cohort Study review¹⁹ in charting a higher prevalence of top-heavy triglycerides (2.3 mmol/L or more) with EFV than with NVP. In the D:A:D survey people taking EFV and NVP had nearly equivalent rates of low HDL cholesterol (at or under 0.9 mmol/L), and similar proportions in each group had a total-to-HDL cholesterol ratio at or above 6.5 mmol/L.

How did lipid quotients compare in treatment-naive people randomized to EFV or NVP in the 2NN study? An analysis comparing 417 people who took NVP with 289 who took EFV for 48 weeks declared NVP the clear lipid winner²⁰ (Table 6). Nevirapine's handsomer lipid profile held true -- or even improved -- after statistical adjustment for changes in viral load and CD4 count. That finding, the 2NN team explained, indicates "an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection."

Finally, Reiss advised, clinicians must consider a person's fat abnormalities when deciding whether to swap a PI for NVP, EFV, or ABC. Those trades have a harder time righting unbalanced lipids in people with moderate to severe lipoatrophy or moderate to severe lipohypertrophy, results of a randomized trial suggest.²¹

Lipids Look for Pretreatment Baseline

Reiss counseled colleagues to remember that HIV itself -- before the body ever experiences antiretrovirals -- upsets lipids. And the longer infection lasts, the farther those lipids stray. When treatment begins, at least some lipid flux reflects a healthy redialing to baseline lipid settings. People with more advanced disease when they start antiretrovirals spin the reset dial farther than people with milder HIV infection. Clinicians should invoke this rule of thumb when comparing lipid seesaws across trials because study populations often differ in disease progression.

Multicenter AIDS Cohort Study (MACS) researchers showed that total cholesterol (-30 mg/dL [-0.78 mmol/L), HDL cholesterol (-12 mg/dL [-0.31 mmol/L]), and LDL cholesterol (-22 mg/dL [-0.57 mmol/L]) all dropped from pre-HIV values when men become infected.²² After treatment began the MACS team traced big rebounds in total cholesterol (+50 mg/dL [1.30 mmol/L]) and LDL cholesterol (+21 mg/dL [0.54 mmol/L]. Mean HDL cholesterol levels languished below baseline in the early months of antiretroviral therapy.

Whether interpreting trials or treating patients, clinicians must also consider two other factors when clocking lipid changes, Reiss added. First, treatment-induced body fat swings affect lipid levels. Research ties both lipohypertrophy and lipoatrophy to surging lipids.²³ Second, the NRTI in the regimen can drive lipids. The randomized comparison of TDF with d4T (plus 3TC and EFV) in treatment-naive people found significantly higher triglycerides, total cholesterol, and directly measured LDL cholesterol after 144 weeks in the d4T group (P < 0.001 for all comparisons).²³ But people taking TDF gained significantly more "good" HDL cholesterol (P = 0.003).

Rating Cardiovascular Risk

Bundling advice from expert panels, Reiss advanced the following scheme for rating and tracking heart disease risk in people with HIV:

• Estimate overall cardiovascular risk

  • Gauge fasting measures before starting or switching antiretrovirals, then every three to six months afterwards, and finally once a year in people on a stable regimen

    • Measure total, HDL, and LDL cholesterol, triglycerides, and glucose

    • Give an oral glucose tolerance test at least to people at risk for type 2 diabetes or with severe lipodystrophy

• Assess all other modifiable cardiovascular risk factors, including:

  • Blood pressure

  • Smoking

This advice rests on algorithms devised for the general population, not for people with HIV infection. Ongoing mega-cohort work like the D:A:D study may eventually yield HIV-specific guidelines. But until then, Reiss assured colleagues, it looks like general models work for people with HIV. Applying the Framingham Heart Study risk equation to MI incidence in the D:A:D cohort plotted a near overlap between predicted and observed heart attacks through four years of potent antiretroviral therapy.²⁴ But Reiss warned that values derived from models such as Framingham may underestimate risk in people with HIV.

What should clinicians do if the heart disease risk looks high relative to the risk of AIDS (as defined by the ART Cohort Collaboration²⁵)? Reiss offered a management tree adapted from advice by Steven Grinspoon (Harvard Medical School, Boston) and Andrew Carr (St. Vincent's Hospital, Sydney)²⁶ (Figure 1).

Groping for Lipodystrophy Predictors

Understanding predictors -- and possible remedies -- for HIV-related body fat changes remains a tall order, conceded Esteban Martínez (Hospital Clinic, Barcelona). And that's not just because lipodystrophy is a new and motley syndrome. Environmental factors, genetics, HIV, and antiretrovirals all make their contribution (Figure 2). And scant data so far shed light on environmental or genetic variables. On top of that, unlike bad lipids, body fat abnormalities have no standard definition.

But research continues to etch out slow advances in understanding subcutaneous fat loss (lipoatrophy) and central fat buildups (lipohypertrophy). On the genetic front, for example, Simon Mallal (Centre for Clinical Immunology and Biomedical Statistics, Perth, Australia) and colleagues linked a gene flip in tumor necrosis factor-alpha (TNF-α) to a higher risk of lipoatrophy.²⁷

Though HIV clinicians aren't set to start probing for single nucleotide polymorphisms, they already routinely measure triglycerides, and pretreatment levels of those lipids also predicted lipoatrophy in people taking extended- or immediate-release d4T.²⁸ Pretreatment fasting triglycerides at or below 200 mg/dL independently predicted a lower risk of lipoatrophy after more than 100 weeks of follow-up, as did age under 40 years and d4T therapy. But this 877-person analysis could not tie a familiar array of variables to lipoatrophy -- gender, race, baseline body mass index, fasting glucose, waist circumference, baseline CD4 count, and viral load.

A growing mound of evidence implicates HIV infection itself in lipoatrophy. A US study comparing HIV-infected people with a general population cohort clearly showed that men with HIV -- though still naive to antiretrovirals -- have a higher risk of fat atrophy than men in the non-HIV group (P < 0.01).²⁹ The HIV Outpatient Study (HOPS), which tracks people in several US HIV clinics, charted a growing incidence of lipoatrophy with each lower bracket of CD4 count nadirs.³⁰ Comparing 384 gay men with HIV and 314 without HIV, MACS researchers confirmed the rarity of lipoatrophy in uninfected people.³¹ While 20% of infected men taking antiretrovirals had subcutaneous fat wasting, only 1% of the HIV-uninfected group did.

Gender Differences in Lipodystrophy Risk?

Several studies determined that women have a higher risk of lipodystrophy, depending on how one defines the syndrome. If one uses the proposed case definition of a mixed syndrome³² and applies it to people in the Gilead Sciences trial of TDF versus d4T, women had a 3.71 times higher risk of lipodystrophy than men (95% CI 1.67 to 8.25) in a multivariate analysis (P = 0.001).³³

Two Italian studies found a higher risk of fat accumulation or mixed lipodystrophy in women than in men.^34,35 But men and women had an equivalent risk of lipoatrophy,³⁴ which proved the predominant fat abnormality in men.³⁵ One of these studies also suggested that fat changes happen faster in women than in men with HIV.

What might explain this higher fat abnormality risk in women? One possibility may be that at least some nucleosides -- including AZT -- reach significantly higher triphosphate levels in women's cells than in men's.³⁶ As a result, Martínez suggested, some antiretrovirals may be more potent, and more toxic, in women. But that cannot be the whole explanation, he proposed, because research shows women also endure more side effects from other drugs, such as psychotropics. And if women specifically metabolize NRTIs better than men, one would expect more lipoatrophy in women, not more fat buildups.

Scarce Remedies for Lipodystrophy

Reversing lipodystrophy remains a mammoth challenge -- especially when many still disagree on lipodystrophy's definition. In notes prepared for the IAPAC Sessions, Brian Gazzard (Chelsea and Westminster Hospital, London) squarely raised the most perplexing question: Does lipohypertrophy exist?

Lots of people with suddenly large bellies have one answer, but the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) famously posited data to the contrary. As sessions attendees pondered Gazzard's challenge, the FRAM team published their long-mulled findings.²⁹ Defining lipohypertrophy as agreement between a participant's report of fat buildup and physical exam evidence, FRAM found that men with HIV have a lower rate of central lipohypertrophy (40.2%) than do men of the same age from the general population (55.9%) (P < 0.001). FRAM data on women remain unpublished.

Nonetheless, Nelson (who presented Gazzard's talk because of the bomb-induced flight delay) concurred with legions of lipohypertrophic people that the problem does exist. But most agree it probably has nothing to do with lipoatrophy. Among HIV-infected FRAM men, hypertrophy did not correlate positively with atrophy (odds ratio [OR] 0.71, 95% CI 0.47 to 1.06, P = 0.10). In other words, HIV-infected men with lipohypertrophy were no more likely to have atrophy than were HIV-infected men without hypertrophy.

And stopping a PI does not make excess central fat melt away, as Martínez³⁷ and several other research groups showed in switching people from a PI to an NNRTI or ABC. But, Martínez explained, these findings do not vindicate PIs from a role in fat atrophy. The ACTG 384 statisticians proved that when they compared 64-week limb fat losses in treatment-naive people randomized to start the PI NFV or the NNRTI EFV.³⁸ In a subset of 157 people with fat changes measured by dual-energy x-ray absorptiometry (DEXA), those taking NFV had a median 13.1% limb fat loss while those taking EFV gained a median 1.8% (P = 0.003). In a logistic regression model adjusted for age, gender, race/ethnicity, baseline body mass index, viral load, CD4 count, and NRTIs used, taking NFV rather than EFV proved a nearly significant predictor of limb fat loss (P = 0.06).

Though ousting a PI may not reverse fat upsets, benching d4T and possibly AZT can add fat to skinny arms and legs. A thymidine analog tradeoff remains the longest-tested limb atrophy-reversing strategy, with follow-up to 104 weeks in the MITOX study.³⁹ But most people who could stop d4T did so long ago and, as Martínez noted, post-switch gains in subskin fat come so slowly that many feel disappointed.

People still taking 40 mg of d4T daily have three choices -- live with the side effects, swap d4T for another drug, or lower the dose. A study that randomized people to continue 40 mg of d4T twice daily, trim back to 30 mg twice daily, or switch to TDF logged a significant six-month limb fat gain with TDF (P = 0.003).⁴⁰ People who eased the d4T dose by 10 mg twice a day also gained limb fat, but not significantly more than people who stayed with 40 mg (P = 0.124). Martínez said the difference between the 40-mg and 30-mg groups remained insignificant at 48 weeks.

If someone wants to trade d4T for another NRTI, what's the best choice? A randomized trial involving people who swapped d4T or AZT for ABC or TDF found equivalent 48-week limb fat gains in the two arms.⁴¹ But fat refills are not the only concern when replacing a thymidine analog. This study also found more toxicity dropouts in the ABC arm (six versus one) and significantly better lipid fixes with TDF.

What about trying drugs that tinker with purported lipodystrophy mechanics? The record here offers little grounds for optimism, Martínez argued (Table 7). Even if a metabolically aimed drug does patch one problem, it often provokes another. And any added drug may have unhappy interactions with antiretrovirals.

Although implants can remedy facial atrophy, Martínez listed several unknowns or disadvantages with this approach: Long-term results remain unverified. No one knows which method works best for which person. All techniques require a trained professional. All are expensive. And most European countries won't pay the bill.

(At the 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, held a few weeks after IAPAC Sessions, researchers showed that uridine⁴² or pravastatin⁴³ reverses fat loss in antiretroviral-treated people and that switching from d4T or AZT to TDF or ABC restores some facial fat.⁴⁴)

Antiretrovirals: One Liver Threat Among Many

All antiretroviral classes -- even, we latterly learned, the entry inhibitors⁴⁵ -- may rock the liver. That's a threat to everyone who needs these drugs, but especially to people coinfected with hepatitis B or C virus (HBV or HCV). And there are lots of them in Europe, reported Jürgen Rockstroh (University of Bonn, Germany), who chaired the IAPAC Sessions talks on hepatitis and HIV.

Among 5,883 members of the EuroSIDA cohort with a hepatitis B surface antigen (HBsAg) test at enrollment, 530 (9%) had a positive test. A similar HBV coinfection prevalence applies in the United States, Rockstroh noted. Hepatitis C prevalence stands even higher in EuroSIDA, at about 33% across the continent. Rates range from 19.6% in central Europe to 46.9% in eastern Europe. And HCV coinfection prevalence will climb even higher in eastern countries, Rockstroh predicted, as HIV spreads among injecting drug users (IDUs).

Grade 4 adverse events -- also known as really bad side effects -- now outrank AIDS as complications of HIV infection.⁴⁶ And the most common egregious "events" involve the liver. A survey of severe side effects in 2,947 people at five US clinical trial sites counted 2.6 liver-related insults per 100 person-years, followed distantly by neutropenia (1.5 cases per 100 person-years), anemia (1.1 cases), cardiovascular disease (0.9 cases), and others.⁴⁶ Collating data from France, Italy, Spain, and the United States, José Arribas (Universidad Autónoma, Madrid) traced steep jumps in death due to HCV-related end-stage liver disease with the dawn of triple antiretroviral therapy:

• From 13% to 35% in Brescia

• From 11.5% to 50% in Boston

• From 4.8% to 45% in Madrid

• From 1.5% to 14% in France

These scary trends don't mean antiretrovirals suddenly started killing people with hepatitis coinfection in 1996. Relative leaps in liver-related deaths reflect lower mortality from opportunistic infections and cancers. And, of course, antiretrovirals remain only one of many liver threats in people with HIV. At the same time, Arribas explained, several factors complicate the understanding of liver toxicity in people taking antiretrovirals:

• Hepatotoxic injuries are poorly understood

• Multiple drugs are involved

• Cholestasis (hampered bile flow) is probably underreported

• Both cohort studies and randomized controlled trials have important methodologic shortcomings

• Long-term follow-up is rare

Complicating matters further, even liver experts don't really understand what elevated transaminases mean. They know even mild elevations forebode progressive liver fibrosis in people with HBV, HCV, and alcoholic and nonalcoholic fatty liver disease, Arribas said. But no one has long-term data on what drug-induced transaminase spurts portend. And most liver enzyme leaps -- even five times a lab's upper limit of normal -- may cause no symptoms. Antiretroviral toxicity probably explains only a fraction of such flares, Arribas proposed. More can be traced to other drugs, infections, alcohol, immune reconstitution, or the chafing hum of "background noise."

RTI-Related Liver Toxicity

Nucleoside reverse transcriptase inhibitors probably rile the liver by depleting mitochondrial DNA, and the worst offenders are ddI and d4T, especially when combined.⁴⁷ Ribavirin (RBV), the anti-HCV drug, worsens NRTI-mediated mitochondrial mixups and should not be teamed with ddI. In the APRICOT trial of pegylated interferon (PEG-IFN) with or without RBV for HCV coinfection, ddI quadrupled the risk of hepatic decompensation.⁴⁸

Arribas listed four signals of NRTI-induced liver damage:

• Unspecific symptoms including abdominal pain, right upper quadrant pain, vomiting, and anorexia

• Hepatomegaly (enlarged liver)

• Mixed cholestatic-hepatocellular liver enzyme pattern: elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and alkaline phosphatase (AP)

• Evidence of extrahepatic mitochondrial toxicity (metabolic acidosis, bicarbonate loss, abnormal amylase, lipase, creatine kinase, or lactates)

Abacavir appears to have a clean mitochondrial slate, but hypersensitivity reactions to this NRTI -- and to the NNRTIs -- threaten the liver. Pregnant women with HIV also run a risk of antiretroviral-related hepatotoxicity signaled by climbing transaminases, cholestasis of pregnancy, lactic acidosis with hepatic involvement, and the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). The US Food and Drug Administration (FDA) counted six liver-related deaths of antiretroviral-treated pregnant women from 1998 through 2003, three of them taking NVP plus AZT/3TC, two taking NVP plus ddI/d4T, and one on NFV plus ddI/d4T.⁴⁹

In the randomized 2NN study comparing EFV, NVP once or twice daily, and EFV/NVP (all with d4T/3TC), rates of grade 3 or 4 liver toxicity proved much lower with EFV (4.5%) than with NVP twice daily (8.3%), EFV/NVP (9.1%), or NVP once daily (13.6%).⁵⁰ Researchers pinned two liver-related deaths on NVP.

In the IDU-rich Johns Hopkins HIV cohort, grade 3 or 4 hepatotoxicity affected 15.6% taking NVP versus 8.0% taking EFV.⁵¹ Of the 564 people studied, 43% had HCV coinfection and 8% HBV coinfection. Coinfected people had a higher risk of liver toxicity, as did people combining an NNRTI with a PI.

A cross-sectional study of 152 HCV-coinfected people in Seville, Spain, charted a 2.56 times higher RR of stage 3 or 4 liver fibrosis with NVP, compared with lower risks among people taking EFV (RR 0.7) or a PI (RR 0.39) and among people younger than 21 years old (RR 0.39).⁵²

PIs' Impact on Hepatotoxicity

Ritonavir-boosted PI therapy does heighten the risk of liver toxicity, but the risk appears to depend on what PI gets boosted. That conclusion emerged from a 1,001-person prospective study of people with or without HCV coinfection in a US cohort.⁵³ After tracking hepatotoxicity for up to 60 months, Johns Hopkins researchers found no higher risk of severe toxicity (AST or ALT more than five times the upper limit of normal) with LPV/RTV or with unboosted NFV. But people taking IDV/RTV had a 2.97 times higher risk of liver trouble and those taking 400/400 mg SQV/RTV twice daily had a 2.41 times higher risk. Coinfection with HCV upped the odds of severe liver toxicity 1.82 times, a viral load above 10,000 copies/mL raised the risk 4.77 times, and a CD4 count above 200 cells/mm³ halved the risk.

Notably, 83% of people with HCV coinfection in this cohort did not suffer antiretroviral-induced liver injury. But coinfection approximately doubled the risk of severe liver toxicity among people taking SQV/RTV, LPV/RTV, or NFV, but not IDV/RTV (Figure 3).

A retrospective analysis of 560 Dutch people taking antiretrovirals found that full-dose RTV quintupled the risk of grade 4 liver enzyme leaps.⁵⁴ But a boosting RTV dose of 200 mg twice daily or less did not inflate toxic markers in this cohort. All told, this study picked out seven independent predictors of grade 4 AST or ALT (at the following hazard ratios [HR] and 95% CIs):

• Female gender: HR 2.8 (1.3 to 5.8)

• Baseline ALT (per 10 U/L increase): HR 1.05 (1.01 to 1.11)

• Chronic HCV infection: HR 5.0 (2.3 to 10.7)

• Chronic HBV infection: HR 9.2 (4.1 to 20.6)

• Recent discontinuation of 3TC: HR 6.8 (2.1 to 22.7)

• Starting NVP in past 12 weeks: HR 9.6 (3.2 to 28.3)

• Starting full-dose RTV in past 12 weeks: HR 4.9 (2.0 to 12.1)

Arribas reminded colleagues that both IDV and atazanavir (ATV) can cause unconjugated hyperbilirubinemia, and the risk is higher in people with hepatitis, added Rockstroh. He avoids ATV after liver transplants or in people with hepatic decompensation -- not because of toxicity but because the high bilirubins complicate clinical management. Stefan Mauss (Center for HIV and Hepatogastroenterology, Düsseldorf) noted that coinfected people take a dim view of ATV-induced yellow eyes because it signals their liver disease to others.

Preventing and Managing Liver Toxicity

Clinicians can take several steps to lower the risk of hepatotoxicity in people with HIV, Arribas proposed, starting with remembering that the risk is higher in women, people with an earlier episode of liver toxicity, obese patients, and of course those with hepatitis coinfection. He suggested the following protocol when sizing up a person's liver toxicity risk:

• Carefully check all baseline characteristics

• Measure aminotransferase levels

• Establish a history of preexisting liver disease

• Consider

  • Concomitant medication and over-the-counter products

  • Alcohol consumption

  • Potential for drug abuse

  • Vaccination against hepatitis A virus (HAV) and HBV

For people who run a higher risk of liver toxicity, pick antiretrovirals that do not swell that risk -- AZT, 3TC, ABC, TDF, and FTC among the NRTIs; NFV and LPV/RTV among the PIs; and EFV if considering NNRTI therapy. Current guidelines spell out dosing advice for certain antiretrovirals given to people with hepatic insufficiency (Table 8).

Arribas recommended checking aminotransferase levels two, four, and 12 weeks after starting a new regimen in people without liver disease. If levels are stable at those points, recheck every three months. In people who have liver disease when they start antiretrovirals, check aminotransferases every two weeks during the first three months of a new regimen, then every three months if stable. Skin rash at any point should signal ALT and AST readings.

What should you do if liver enzymes do rise? Jumps below five times the upper limit of normal are generally safe to tolerate -- if they're asymptomatic and you exclude hypersensitivity reaction. Arribas listed three reasons to stop antiretrovirals: symptoms of liver disease, escalating lactates, and evidence of severe liver dysfunction such as coagulopathy or encephalopathy. Severe liver injury should prompt a search for a cause other than antiretroviral therapy.

Treatment Options for HBV and HCV

With HIV, seroconversion is a bad thing. But with HBV, hepatitis B e antigen (HBeAg) seroconversion is a very good thing, linked as it is to longer survival.⁵⁶ Yet studies across Europe, reported Mauss, show that HBeAg-negative ("precore mutant") chronic HBV infection has become more prevalent. That's bad news because HBeAg-negative HBV carries with it a higher risk of cirrhosis than HBeAg-positive infection. Hepatitis textbooks, Mauss cautioned, have yet to reflect this change.

Treatment options for chronic HBV fall into two bins -- PEG-IFN and HBV polymerase inhibitors, which often double as nucleoside or nucleotide inhibitors of HIV reverse transcriptase. Interferon, Mauss explained, is an option only for HBeAg-positive people without marked cellular immunosuppression (Table 9). Because polymerase inhibitors act independently of cellular immune status, they are the choice after cellular immunosuppression sets in.

Lamivudine, the prototype polymerase inhibitor, boasts a long ledger of success in controlling HBV. But rapid evolution of HBV resistance to this drug limits its value as monotherapy. Resistance emerges more slowly to adefovir, but some people may not respond to the drug, and resistance to adefovir seems likely to confer cross-resistance to more potent polymerase inhibitors.

Tenofovir ranks as one of those more potent polymerase stiflers, and resistance emerges slowly to this drug. A placebo-controlled trial comparing TDF with adefovir in HIV/HBV-coinfected people yielded 48-week evidence favoring TDF.⁵⁷ Entecavir, Mauss predicted, will become an option for people who need no antiretrovirals. But entecavir does a poor job of controlling lamivudine-resistant virus.

Emtricitabine, licensed for HIV infection, has activity against HBV. Other polymerase inhibitors in development are telbivudine (LdT), clevudine (L-FMAU), elvucitabine (LFd4C), valtorcitabine (Val-LdC), and amdoxovir (DAPD).

Reverse transcriptase inhibitor monotherapy proved fruitless -- even disastrous -- against HIV. What's keeping HBV experts from taking a harder look at polymerase inhibitor combos? So far, Mauss explained, research on anti-HBV combinations has turned up scant evidence supporting this strategy, though the superior efficacy of multidrug regimens remains "theoretically convincing."

A trial of lamivudine plus adefovir versus lamivudine alone in HBeAg-positive treatment-naive people without HIV discerned no HBV DNA load difference between the regimens after 52 weeks. Resistant virus did emerge more slowly in the two-drug group (2%) than in the lamivudine monotherapy group (20%). Perhaps because of overlapping resistance profiles between lamivudine and LdT, combining the drugs in another study did not lower HBV DNA more than LdT alone. And in a third study solo TDF could not outdo TDF plus lamivudine in lowering DNA load or calming liver enzymes.

How these lackluster results will shape the future of anti-HBV therapy is hard to say. What would have happened to antiretroviral planning, for example, if three successive randomized trials failed to demonstrate the inferiority of AZT monotherapy?

In contrast, combination therapy with IFN and RBV has nailed down a standard-of-care slot for HCV infection, regardless of coinfection with HIV. When completed, the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) trial of PEGIFN plus RBV in coinfected people yielded the best sustained virologic response (SVR), 40%, in any study of people burdened by both viruses -- even though the RBV dose (800 mg daily) was low according to current thinking.⁵⁸

Yet this SVR lags those evoked in people without HIV infection, and only 29% of coinfected people with HCV genotype 1 managed a sustained response. In a later and much smaller study of PEG-IFN plus a weight-adjusted RBV dose of 800 to 1,200 mg daily, the SVR came close to 40% in people with genotype 1 or 4 and exceeded 50% in those with genotype 2 or 3. Mauss argued that this weight-tempered RBV dose should be the standard of care in HIV/HCV-coinfected people. He also cited histologic improvement in APRICOT enrollees without an SVR to argue that it may be unethical to withhold anti-HCV therapy from coinfected people with early cirrhosis, because they may stand to gain the most from treatment.

The APRICOT trial also showed that clinicians can predict failure to attain an SVR with PEG-IFN plus RBV after only three months of treatment. Among people randomized to those drugs, 85 (29%) did not have an early virologic response. Of those early nonresponders, only two (2%) went on to notch an SVR. The financial and toxic costs of this regimen are probably too high for early nonresponders.

Is PEG-IFN/RBV a feasible regimen for people on opioid maintenance therapy? Results of the first controlled trial of this strategy in people with chronic HCV infection (but not HIV) suggests the answer is yes.⁵⁹ Mauss and colleagues recruited 50 people on methadone maintenance for at least six months and 50 with no injecting drug use or opioid maintenance for at least five years. They matched the groups for gender, age, HCV genotype, and HCV RNA load. People with genotype 2 or 3 got 1.5 µg/kg of PEG-IFN alfa-2b weekly plus 1,000 to 1,200 mg of RBV daily for 24 weeks. Those with genotype 1 or 4 took the same regimen for 48 weeks.

Although the end-of-treatment response proved significantly better in the nonopioid control arm, the groups did not differ in SVR (Table 10). A substantially higher proportion of people in the methadone maintenance arm (about 50%) than in the control arm (about 20%) did stop antiviral therapy. But methadone maintenance enrollees with an SVR managed to lower their methadone dose during the trial.

Mauss concluded that careful selection of HCV-infected people for PEG-IFN therapy and active management of side effects will maximize the impact of treatment.

New Antiretrovirals, New Targets

Compared with clinicians treating HBV and HCV, those focused solely on HIV hold a royal flush of treatment options. For people just starting antiretroviral therapy, that has made life easier, and longer, but nonetheless more vexing than it would be without a retrovirus locked forever in their T cells. As Clumeck opined when opening the IAPAC Sessions talk on side effects, the key to any new antiretroviral may now be durable tolerability.

But for people with plenty of resistant virus immured in mononuclear vaults, priorities change. They need a drug that reins in that resistant virus, and they need one or two more drugs to harness other strains in their dodgy quasispecies. Drug developers do their best to fashion physics for resistant virus, but these new meds have their limits. Lange -- pressed into service when air delays grounded the designated speaker, Schlomo Staszewski (JW Goethe University, Frankfurt) -- cited tipranavir (TPV) and TMC 114 as PIs that parry resistant virus well. But once a handful of mutations pile up, these PIs' potency fades. And they carry toxic baggage that few would tolerate in a first-line drug.

Meanwhile, the hunt for agents that hit new targets shows few signs of slowing -- despite the chancy odds on devising peppy and more-or-less palatable drugs to fit a narrow niche. Inhibitors of viral attachment, entry, integration, and maturation all vie for the attention of investors, reporters, and -- perhaps one day -- clinicians. But the urgent need for such remedies has barely shortened their road to approval.

HIV integrase inhibitors have tantalized drug makers since scientists crystallized the enzyme's structure over a decade ago. Because the current crop of candidates inhibits DNA strand transfer, Lange noted, they may be called STIs. That acronym seems certain to foment further confusion in headlines on structured treatment interruptions and sexually transmitted infections. But it would be nice if that were the biggest worry about this problem-plagued class. The long-suffering Merck and Company team did midwife an integrase inhibitor that knocked down viral loads 1.7 log copies/mL -- all by itself -- in treatment-naive or currently untreated people. But Merck had to abandon this prodigy because of toxic threats. (A few weeks after IAPAC Sessions, the same team unveiled data showing 2-log [100-fold] drops after 10 days of monotherapy with its newest integrase inhibitor, MK-0518.⁶⁰)

Maturation inhibitors do the same thing PIs do, Lange explained, preventing viral bits and pieces from melding into mature virions. But they do so at a different step in HIV's Homeric life cycle. The maturation muffler PA-457 looked good in a 10-day placebo-controlled monotherapy study, trimming viral loads in eight of 12 people who took the drug.⁶¹ But toxicity studies in animals have been hard to mount.

TNX-355, a monoclonal antibody that smothers CD4 receptors, garnered interest when a 10-mg/kg dose lopped a median 1.5 log copies/mL off the viral loads of treatment-experienced people in a phase 1 dose-finding study.⁶² The drug is a humanized monoclonal antibody with a long half-life. Viral loads in the 10-mg/kg group kept going down for 14 days after a single injection.

Coreceptor Rejector Conundrums

The front-running CXCR4 coreceptor antagonist appears to be AMD 070, tested in humans at 50, 100, 200, and 400 mg. But Staszewski and Lange noted several potential drawbacks to drugs that target the X4 coreceptor:

• X4-tropic virus surfaces mainly in people with advanced infection.

• Most people with X4 virus have a mixed viral population that includes R5-tropic HIV.

• Clinical benefits of inhibiting X4 virus alone remain unknown.

• The safety of X4 antagonists has not been verified.

The viral population never shifts from R5 to X4 virus in about half of all people infected with HIV-1 subtype B. X4 virus hardly ever crops up in people infected with the globally dominant HIV-1 subtype C, Lange noted. In Chelsea and Westminster Hospital's London cohort -- 19% of whose members carry non-B virus -- HIV-1 subtype did not influence coreceptor use.⁶³ Multivariate analysis in this study linked higher CD4 count, higher natural killer cell count, and lower viral load to R5 tropism.

Lange warned that discussion of viral coreceptor tropism often gets fuzzy because many misuse the term "dual tropic." Strictly speaking, dual-tropic virus can grasp either X4 or R5 coreceptors (Figure 4). But when speakers say "dual tropic" they often mean a "mixed-tropic" viral population -- that is, an ensemble of single-tropic X4 and R5 viruses. Research shows clear distinctions between virus that prefers the X4 coreceptor and virus that fancies R5 (Table 11).

Lange noted that AZT preferentially phosphorylates to its active metabolite in activated T cells. In other words, the drug works mainly against R5-tropic HIV. Zidovudine monotherapy studies showed that the NRTI can push the viral population from preferring R5 to preferring X4. On the other hand, ddI phosphorylates mainly in resting T cells and so exerts most of its antiviral activity there. It can push an X4 population back toward R5.

Traits such as these, Lange argued, could help pick the best partners for CCR5 antagonists. For example, AZT may prove a less desirable partner for CCR5 antagonists because both drugs could egg an R5 viral population toward a possibly more dangerous X4 tropism. Such fateful synergies remain to be explored, even as CCR5 antagonists thrum through phase 2 and 3 trials.

Getting a handle on how antiretrovirals drive tropism remains difficult, though, because tropism assays remain rudimentary. Staszewski listed these limitations:

• Tropism assays do not distinguish between dual-tropic and mixed-tropic viral populations.

• Tropism assays do not measure the quantity of virus that has a particular tropism.

• Tropism assays may fail to phenotype 5% to 10% of viral samples.

• Assay failure to detect X4- or R5-tropic virus in plasma does not preclude existence of such virus below the limit of detection or in other anatomical compartments.

Meanwhile, development of CCR5 antagonists proceeds in the face of apparent irony, Lange suggested. Everyone knows that CCR5-tropic virus dominates the viral population from the day of infection throughout its early course. Yet the primary market for these agents consists of people with multidrug-resistant virus -- in other words, people with more advanced HIV infection and thus most likely to have X4-tropic virus. Yet because viral populations in late infection rarely, if ever, use only the X4 receptor, CCR5 antagonists could corral at least part of that population. But the rest of the regimen better bridle X4-tropic virus.

This irony grew richer in recent months when GlaxoSmithKline halted a phase 2 study of its CCR5 candidate in previously untreated people because of acute liver toxicity.⁴⁵ Then the company pulled the plug on all development -- and started shifting trial participants to other antiretrovirals -- after liver enzymes and bilirubin spiked in a treatment-experienced person taking the drug.

Weeks after IAPAC Sessions, Pfizer announced a solitary case of liver toxicity in the nearly 1,000 people exposed to maraviroc. The case involved a person already taking isoniazid and cotrimoxazole before starting maraviroc. Independent safety reviewers believe any of these drugs, alone or together, could have caused the severe liver toxicity, which required transplantation (see note 45). So far Schering-Plough has seen no liver snags in trials of their CCR5 drug, vicriviroc. But Schering-Plough had to shutter a study of treatment-naive people when vicriviroc plus AZT/3TC proved virologically inferior to EFV plus AZT/3TC.⁶⁴ The company says it will continue testing its CCR5 antagonist -- with backbones other than AZT/3TC -- in antiretroviral neophytes.

As in other antiretroviral classes, cross-resistance threatens CCR5 antagonists. But work so far suggests class resistance emerges only when a triazole antagonist fails. Maraviroc, the CCR5 blocker from Pfizer, is not a triazole drug. Viral clones resistant to maraviroc remained sensitive to other agents in this class.⁶⁵

Adherence, Toxicity and Adherence

The meeting organizers recruited the always-provocative Brian Gazzard to share his insights on "maximizing highly active antiretroviral therapy (HAART)." But the World War II bomb unearthed at Schiphol (see above) kept him in London, so attendees saw his slides filtered through his equally piquant colleague, Mark Nelson.

Both see efficacy as a nearly eclipsed issue in antiretroviral development of first-line regimens. Hefty majorities of people starting medleys such as EFV, 3TC, and TDF in clinical trials promptly push their viral load under 50 copies/mL and keep it there. Nelson maintained that good physicians should no longer see new patients slip into triple-class failure. Chelsea and Westminster Hospital arithmeticians count only 100 triple failures in a 4,000-person cohort, though that sterling record owes something, he conceded, to an early preference for later antiretroviral intervention. That policy let Nelson and confreres learn from others' mistakes.

So dogged adherence becomes issue number one, and nothing undoes doggedness like side effects. Echoing other speakers, Nelson splayed side effects into two species -- those we know now, and those we'll learn about later (the buried bombs). Adherence depends partly on a gamut of flexible factors including pill burden, food requirements, day-to-day toxicity, and long-term toxicity -- and partly on more unvarying variables such as a person's behavior and beliefs about health.

But besides a certain antiretroviral's pill tally and tolerability, Gazzard and Nelson noted, clinicians must also weigh the "forgiveness" factor when deciding what to prescribe. Non-nucleosides proved more "forgiving" than PIs because their long half-lives mean one missed dose does not spell rebound doom. But the equation is not that simple, Nelson added, because loss of viral control evokes NNRTI-resistant virus much more readily than PI-resistant virus. So if you suspect shaky adherence in someone starting therapy, do you prescribe an NNRTI because it is more "forgiving," or a boosted PI because it provokes resistance less often in early rebounds? He did not answer that question.

Is today's guideline-favored NNRTI, EFV, better than the guideline-favored PI, LPV/RTV? Gazzard raised that possibility, citing the modest 53% sub-50-copy rate in a 96-week noncompleter-equals-failure analysis comparing twice-daily with once-daily LPV/RTV (plus TDF/FTC).⁶⁶ Nelson added that the disappointing response reflects high dropout rates in both the once-daily arm (37%) and the twice-daily arm (39%), and that toxicity explained about half the dropouts. But toxicity -- Gazzard and Nelson agree -- must rank as a primary concern in treatment planning.

For treatment-naive people, picking between a PI and an NNRTI is only the first hurdle, Nelson reminded colleagues. Among the many gems mined from ACTG 384 was the clearly superior potency of EFV when backed by AZT/3TC instead of ddI/d4T.⁶⁷ Sinking virologic response curves for EFV plus ddI/d4T overlapped those for NFV plus either ddI/d4T or AZT/3TC, with the response to EFV/AZT/3TC remaining significantly better. One could quibble that ddI/d4T looks like a straw man backbone in hindsight. But a more recent contest between AZT/3TC and TDF/FTC, again with EFV, clearly showed the newer duo's superiority.⁶⁸ Better backbones make better third drugs better.

Gazzard and Nelson discriminated between finding a potent, tolerable regimen and finding an "easy" regimen. The ACTG A5095 protocol⁶⁹ -- and a raft of other studies -- proved that point to the dismay of many. Triple-NRTI regimens, despite their convenience and other, theoretical, attributes, came up short against EFV-based combos in trial after trial. "You can't be too patient oriented," Nelson cautioned.

These studies make a larger point than the relative frailty of triple nukes: Good-looking but untested regimens of any ilk -- EFV plus ddI/TDF comes to mind -- carry the risk of rude surprise.

Adherence remains the most-touted but least-tested element of antiretroviral planning. Gazzard stressed the need for continued reinforcement even in prize adherence pupils. Nelson vouched for the value of enlisting nurses and pharmacists in this enterprise.

Although it is politically correct to say physicians cannot predict good adherence, Gazzard counseled, in reality all physicians see more than a few people with "very disturbed behavior." Forcing them into therapy on the grounds that adherence can be taught may be the first knot in a string of failures.

Mark Mascolini writes about HIV infection (markmascolini@earthlink.net).

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