Epidemic (and Lesser) Lessons From Rio Centro: Part 1 -- The Inversions
3rd IAS Conference on HIV Pathogenesis and Treatment, July 24-27, Rio de Janeiro, Brazil
Night falls with a thud in the tropics. Yet the sun rises with circumspection.
Nontropical travelers to the 3rd IAS Conference on HIV Pathogenesis and Treatment, held July 24-27, 2005, in Rio de Janeiro, learned this when one minute they sat, backs to breakers, breasting the sun's setting rays -- and the next minute they groped hotelward in spryly dying light. Rio de Janeiro lies just degrees north of the Tropic of Capricorn, but far enough to ensure tropical climes in July (the dead of winter) and this scuttling afternoon sun.
What explains this wry inversion of expectations for those rooted to Earth's more boreal reaches? AIDS conference crawlers, if not scientists, at least aver a scientific bent and should know stuff like this. We vaguely grasp that the tropical sun's less wayward year-round arc has something to do with it. But what exactly?1
Then there are those preposterous downtown peaks -- Sugar Loaf et al -- that wrench gasps of admiration even from tourists well prepared for these iconic monoliths. Sheer promontories in center city -- decidedly nonvolcanic islands stuck squarely inland -- invert long-held notions of geographical propriety. We may cablecar to their summits and watch the sun tumble with yet greater drama. But who among the science-minded can construe their ancestry?2
Rio, even the blinkered attendee soon saw, abounds in ripe inversions of ready presumption. Unlike most cities where the wealthy build on hills to reap clean air and views, in Rio the poor command the aerie prospects too treacherous for massy mansions. And anyone expecting a river in Rio had best consult the plucky Portuguese navigators keen enough to chart a winter Atlantic crossing but -- arriving on January 1, 1502 -- incurious enough to see if a mouthing river really explains Rio's roomy Guanabara Bay.3
Another geophysical inversion: About an hour after boarding buses for the conference center, attendees learned that the site, "Rio Centro," is not in central Rio. Or even the near suburbs, apparently. But this disappointed propinquity had its merits: all the more time to canvass abstracts, map the day's itinerary, or mull a career jump to Brazilian traffic planning.
And in perusing those abstracts one soon deduced a happier inversion: A copious load of conference reports came from tropical and subtropical lands with lush HIV epidemics. That means much more at this biennial IAS conclave, because the conference focuses solely on basic and clinical research, leaving socioeconomic worries to the interleaved International AIDS Conferences.
Of the 803 reports at the 1st IAS Conference on HIV Pathogenesis and Treatment, held in Buenos Aires in 2001, 193 came from countries other than the United States, Canada, Australia, Japan, Israel, and those in western Europe. Rio outdid that 1-in-4 ratio with 565 reports from poor or middle-income countries versus 1,421 from western Europe and allied plutocracies -- a 2-in-5 ratio.
Then there were those most important inversions -- the dashed or endorsed expectations that reverse or confirm hopes of bringing HIV to heel. Rio offered rich examples, which this article and a later report [in the December 2005 IAPAC Monthly] will explore:
Everyone knows certain measures ward off HIV. Or do they? With mountains of cohort data nominating circumcision as a likely expedient for lowering HIV incidence in men, the first randomized trial of foreskin trimming found that -- yes, indeed -- it makes HIV infection less likely. But researchers bent on proving that mutilating female circumcision heightens HIV risk in women could not explain away numbers that argued the opposite.
Work from California showed that human papillomavirus (HPV) infection bolsters the odds of HIV infection via anal sex between gay men, while research on the other side of the continent confirmed high risks of transmitted drug-resistant virus. Countering steady trends in adult studies, a large European pediatric trial found that resistance testing did not help pick better rescue regimens for kids.
Is Circumcision the Kindest Cut?
Maybe this conference's most important report came in a slide session on sexual transmission of HIV, when Bertran Auvert (University of Versailles Saint-Quentin, France) unveiled the first randomized trial evidence that circumcision limits HIV risk in heterosexual men [abstract TuOa0402]. That conclusion seemed a cinch since one cohort study after another buttressed commonsensical notions that foreskin snipping may stymie HIV in several ways:4
But all the good reasons in the world don't add up to proof. Only randomized controlled trials crank out evidence physicians can confidently take to the clinic. Auvert's trial is not the only randomized effort to test circumcision's value. But it is the first to yield results.
Auvert recruited 3,128 healthy men without HIV infection in Orange Farm, an urban enclave near Johannesburg, South Africa. There are no oranges, Auvert averred, and there is no farm. But there's lots of HIV infection: Adult prevalence stands at 32%. These 18- to 24-year-olds were randomly assigned to undergo circumcision by a physician or to remain uncircumcised. Everyone agreed to follow-up visits three, 12, and 21 months after randomization, when workers tested them for HIV and drummed in safe sex lessons.
All enrollees could opt for foreskin fleecing after 21 months, but follow-up didn't last that long for most. Preliminary results convinced trial watchdogs to stop the study early when HIV incidence in the control group rose disproportionately fast. After 4,664 person-years of follow-up, Auvert counted 51 infections among uncircumcised men and 18 in the circumcised group. That put incidence at 2.2 HIV infections per 100 person-years in the control group versus 0.77 with circumcision.
In an analysis not adjusted for confounding variables, the circumcised men had a 65% lower risk of HIV infection. Adjusted analyses showed similar rates of protection in the intervention group (Table 1). Auvert figured that foreskin removal spared six or seven of 10 men from HIV infection.
Just as surely as foreskin clipping seems a safe bet to cut HIV transmission in men, so the various bloody ablations labeled female circumcision seem certain to lift transmission risk in women. The tainted lancets often used in these rough-and-ready surgeries may carry HIV from one woman to the next; the resulting genital lacerations are open doors to pathogens of any ilk; and women recovering from circumcision may turn to more risky anal intercourse. But a large survey of Tanzanian women netted the vexing conclusion that female circumcision halved their risk of HIV infection.
Rebecca Stallings (ORC Macro, Calverton, Maryland) set out to see whether variables influencing circumcision or HIV risk could solve this apparent riddle [abstract TuOa0402]. But session attendees guessed Stallings had no good news when she started her talk with a terse avowal of opposition to female circumcision and to government intrusion in women's lives.
Study results rest on capillary blood samples from a nationally representative sample of 15- to 49-year-old women who took part in the 2004 Tanzania Health Information Survey. That cohort included 5,753 women (84%) who agreed to anonymous HIV testing. Stallings used that group to probe for bivariate links between HIV risk factors and both circumcision and HIV serostatus. Then, to adjust circumcision status for factors proving significant in bivariate analyses, she built logistic regression models in a subgroup of 5,284 women who ever had intercourse.
None of the variables Stallings weighed explained why circumcision apparently protected women from HIV in the primary analysis -- and she weighed a lot of them: region, years living there, household wealth, age, education, religion, years sexually active, union status, polygamy, number of recent and lifetime sex partners, recent infection or abnormal discharge, use of alcohol, and ability to say no to sex.
In the final model, circumcision whittled the risk of HIV infection by 40% (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.41 to 0.88). That model also yielded the unsurprising finding that genital ulcer disease for 12 months or more raised the HIV risk 2.20 times (95% CI 1.28 to 3.77). Stallings' study also confirmed that male circumcision has no impact on women's HIV risk. She closed with the slender hope that "anthropological insights on female circumcision as practiced in Tanzania may shed light on this conundrum."
Epidemic Heads for a Second Generation
For some years, epidemiologists have warned that the first generation of infants infected at birth with HIV would soon be old enough to have sex, have children, and transmit the virus on to them. That day arrived a few years ago, reported Michelle McConnell from the US Centers for Disease Control and Prevention (CDC) with colleagues in New Jersey, Puerto Rico, Texas, and US National Institutes of Health (NIH) clinical trials sites [abstract MoPeLB9.5C01].
Gathering facts from chart reviews and interviews from March 2002 to June 2004, the CDC team found 18 pregnant or previously pregnant youngsters infected by their mothers. The group included eight Hispanics and five African Americans with a median age of 18 years (range 15 to 25 years) at the time of the interview. Only five of them (28%) were raised by at least one of their parents.
Among the eight young women who bore a child most recently, all eight did so by cesarean section. Their median CD4 count during pregnancy measured 304 cells/mm3, and they had median viral loads of 7,238 copies/mL when they started prenatal care and 1,554 copies/mL at delivery. All eight were taking antiretrovirals during pregnancy, but only seven did at labor and delivery.
Fifteen of these 18 young women (83%) did not intend to become pregnant. Their median age when they did was 17 years (range 13 to 20 years), and their median age when they first had sex was 15 years (range 10 to 19 years). Of the 23 pregnancies recorded, three are ongoing, one resulted in miscarriage, and nine ended with elective abortion. One of the 10 babies born came into the world with HIV.
Among the 11 women who most recently gave birth or are still pregnant, seven began prenatal care during the first trimester and eight had genotypes for resistance mutations. Genotyping may help clinicians make sure these pregnant youngsters do not pass resistant virus to their infants. But genotyping did not help pick better regimens in a randomized trial of 170 children with a detectable viral load and at least two years of experience with at least two NRTIs [abstract WeOa0106]. Carlo Giaquinto (University of Padova, Italy) and colleagues sniffed out several factors that may explain this surprising result.
Clinicians in Italy, Brazil, the United Kingdom, Spain, Germany, and Portugal randomized 87 children to start a new regimen based on resistance testing and 83 to try a new combination picked without genotyping help. Several adult trials of resistance testing offered clinicians expert advice in interpreting genotypes, and at least two adult studies show that sage counsel pays off.5,6 Although clinicians in Giaquinto's PERA trial could tap steering committee virologists for help, they did not receive expert advice "as a matter of course."
After 48 weeks of rescue therapy, viral load drops averaged 1.23 log copies/mL in the genotyping group and 1.51 log copies/mL in the control group, a nonsignificant gap. This tiny difference dwindled even more by 96 weeks. Nor did the groups differ much in proportions with a viral load below 50 copies/mL at 48 weeks (19% genotyping, 21% control) or 96 weeks (21% genotyping, 18% control). The genotyped group did enjoy a slightly better (2.5%) CD4-cell gain after 96 weeks (P = 0.06).
Why did genotyping flop as a rescue planner in PERA? Giaquinto suggested several reasons in introducing his study -- greater difficulty in suppressing viremia among children than adults, more adherence problems with kids, and fewer antiretroviral options for children. But he also uncovered more specific reasons for genotyping's undoing.
First, substantially more children in the genotyping group (56%) than the control arm (19%) were prescribed didanosine (ddI) and stavudine (d4T) as their NRTI backbone. Why? The VirtualPhenotype assay used consistently signaled viral sensitivity to these NRTIs in the genotyping group, though Giaquinto aptly observed "these drugs are less likely to be sensitive with more prior exposure and this may explain the effect on virological response."
Second, while 49% of genotyped children continued one or more NRTIs from their starting regimen, only 19% in the control group did so (P < 0.01). On the other hand, significantly more control arm children (55%) than genotyped children (43%) recycled one or more drugs from a previous regimen (P < 0.01). The most-continued drugs in the genotyping group were ddI and d4T, while control group physicians usually recycled zidovudine (AZT) and lamivudine (3TC). Numerous studies demonstrate the value of mixing AZT and 3TC and the toxic risk of combining ddI and d4T.
Third, Giaquinto turned up one ironic chit of evidence suggesting that genotyping-arm clinicians would have fared better without test results. Before randomization researchers asked all physicians, "If this child is randomized to no resistance testing, what regimen would you prescribe today?" An overwhelming 82% in of the genotyping docs named at least one drug in this hypothetical regimen that differed from the ones they gave after seeing genotypic results. But only 18% in the control group switched a drug when they actually got around to prescribing (P < 0.001).
If one assumes steering committee virologists would have steered physicians away from ddI and d4T -- understanding the unreliability of phenotypic readings at the time of this 2000-2003 trial -- routine expert advice may have turned the result in genotyping's favor.
On the Prowl With Patient Zero
In his frisson-filled look at the US epidemic's first days, And the Band Played On, Randy Shilts assigned the tag "Patient Zero" to the Canadian flight attendant who purportedly brought HIV to North America and kept spreading it with abandon even after physicians figured something was up and told him to stop.7
Gary Blick (Circle Medical, Norwalk, Connecticut) shared Shilts's knack for melodrama in naming his Rio-leading slide talk "Patient zero: the Connecticut source of the multidrug resistant, dual-tropic, rapidly progressing HIV-1 strain found in NYC" [abstract MoOa0101]. Whether Blick really found the guy whose sex clubbing infected the notoriously bruited "New York City man"8 remains open to question. Although top-tier virologists like Mark Wainberg (McGill University, Montreal) sounded convinced by Blick's data, the virologic jigsaw pieces needed a little hammering to fit.
Blick's candidate had what researchers delicately call "unprotected insertive anal sex" with the New York City man a week before Allhallows Eve in 2004, a night meshing with the New York man's probable date of infection.8 A lot of other guys apparently did the same thing to the New York fellow on or around the same day, but the highly antiretroviral-experienced Connecticut candidate had a viral genome virtually identical to that of the New York virus. And both viruses retained susceptibility only to the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) and the fusion inhibitor enfuvirtide (ENF).
But the New York and Connecticut viruses do differ. Whereas the New York variant can latch onto either the CCR5 or the CXCR4 coreceptor, the Connecticut strain solely snags CCR5. And while the New York virus has a hyper-revved replication capacity of 136% compared with nonmutant virus, the Connecticut virus has only a 41% replication capacity. The latter difference may explain the New York man's full-tilt progression to AIDS, while the presumed Connecticut donor remains a slow progressor.
Whether Blick is right about his Patient Zero matters less than how many Patient Zeros are on the street swapping viruses with known and anonymous paramours. Blick himself counted three -- the New York City man (who kept having sex until he got sick), the Connecticut man, and the Connecticut man's "open-relationship" partner of 12 years, who shares a similar multimutant virus. This partner also ended up on the giving end of anal sex with the New York man last October but claims he didn't ejaculate.
Blick was clued to his patient's potential donor role by QUEST Diagnostics, which spotted a 99.5% pol gene match between his virus and the New York man's strain. At the XIV International HIV Drug Resistance Workshop, held June 7-11, 2005, in Québec City, Canada, Ron Kagan from QUEST reported uncovering 12 sequences from four people (one the Connecticut man) that nearly mirrored the mutations in the New York case -- four out of 153,000 studied.9
An interesting and little-mentioned demographic in the New York case is the man's age. He had reached his late 40s by the time he took home his furious virions. The Connecticut man is even older -- 52 according to Blick's records -- and his steady party companion is 41. These are no wild youths fresh from the provinces and keen to score big in the Big Apple. They're old enough to know something about HIV. And the Connecticut men have taken antiretrovirals for nearly a decade.
The New York man and the alleged Patient Zero share another trait -- fondness for methamphetamine. As reported at the Resistance Workshop10 and again in Rio [abstract MoPpLB0105], that satyrizing stimulant -- and sildenafil (Viagra) -- boost the risk of transmitting resistant virus (see note 10).
At the Rio conference, the same methamphetamine researcher, Peter Chin-Hong (University of California, San Francisco), also unfurled evidence that HPV infection and one of its afterclaps -- atypical squamous cells (ASC) -- up the odds of HIV infection among gay men [abstract TuOa0403]. So gay men who don't get HIV directly from anal sex can get HPV instead and wind up with a higher HIV risk -- not to mention anal cancer. The hypothesized mechanism is easy to understand: HPV-induced anal neoplasia spurs blood vessel growth, bleeding, and recruitment of CD4 and dendritic cells.
Chin-Hong and confreres in three other cities -- Boston, Denver, and New York -- tracked 1,409 sexually active gay men without HIV infection for 36 months starting in January 2001. Monitoring ASC by anal cytology and HPV by polymerase chain reaction (PCR), they found that 64% of the men had HPV infection when they joined the cohort. Their median age stood at 36 years (range 30 to 43 years), 78% were white, 64% had a college diploma, and 35% used old-fashioned poppers (amyl or butyl nitrite). Only 12% used methamphetamine, but the drug independently inflated the risk of HIV infection (Table 2). In the past six months these men had sex with a median of six other guys (interquartile range [IQR] two to 14).
Two multivariate models picked out four independent predictors of HIV infection (Table 2).
Finding HPV and the lesions it causes in gay men could tell physicians they're treating someone who also runs a high risk of HIV infection, Chin-Hong concluded. He called for further study using high-resolution anoscopy to confirm his virologic and cytologic findings.
Resistance, Adherence and Risky Sex
Although the New York City man and his presumed multimutant donor make good headlines (see preceding section), they're merely a frothy whitecap in the churning sea of risky drugs, riskier sex, and resistance transmission. A meta-analysis by CDC math majors found that HIV-infected people who think taking antiretroviral therapy (ART) or having a low viral load prevents HIV transmission run nearly twice the risk of having unprotected sex as people without those beliefs.11 And a clinic-based Connecticut study figured that only 5% of people practicing high-risk sex had resistant virus, but that core group accounted for a high proportion of dangerous liaisons.12
Sonia Napravnik (University of North Carolina at Chapel Hill) extended this research in a study of 303 HIV-infected people that linked both bad adherence and resistant virus to jeopardous sex [abstract MoPp0203]. The study group included 201 men and 102 women, 73 whites and 230 nonwhites, and 22 who abused alcohol. None of those variables swayed the risk of unprotected sex, defined as condom-free sex with one or more partners in the past year. Several other variables did favor unsheathed dalliance:
At least in this North Carolina cohort, four of five infected people still not taking antiretrovirals apparently assume immunity to reinfection with another (possibly resistant) virus, while people taking antiretrovirals are more cautious. Those findings run counter to the meta-analysis finding that people taking antiretrovirals feel less inclined to rely on rubber.11
Napravnik had genotypes on 114 people, 45 of whom (39%) preferred coitus sans condom. Of those 45, 40 (89%) had one or more resistance mutations. The median mutation tally in this group was 4 (IQR 2 to 6), 69% had mutations that knocked out two or more antiretroviral classes, and 27% had triple-class resistance.
Defining "inferior adherence" as missing one or more doses in the past three days, the Chapel Hill team confirmed that trait in 28% of their cohort. Among those iffy pill takers, 66% had unprotected sex versus 46% with perfect adherence. That difference made perilous sex 2.27 times more likely among wobbly adherers (95% CI 1.15 to 4.47) (P = 0.02).
Peregrinations With Mutations
Airplanes have proved remarkably reliable vectors for all manner of epidemic-breeding germs.13 Whether Randy Shilts was right or not about a flight attendant winging the retrovirus into North America,7 HIV's nearly simultaneous debarking in New York, Los Angeles, and San Francisco suggests it came by plane and not tramp steamer. Transborder SARS eruptions two years ago show that pathogens without passports still hop jets with indign impunity. And globe-trotting gays packing HIV as carry-on still pose threats to overseas pickups and regulars back home.
That conclusion came from a small but instructive survey of 64 newly diagnosed gay men from San Francisco [abstract MoPe10.7P13]. With interviews, genotypes, and detuned antibody assays, Hong-Ha Truong (University of California, San Francisco) told a story of high mobility with mutant virus by these recently infected men. The group included 49 (77%) born in the United States and 15 (23%) born elsewhere, two thirds of them white, almost all under 40 years old, and all infected with HIV-1 subtype B.
Defining HIV exposure period as the span between the last negative and first positive HIV test, Truong found that 35 men (55%) lived or traveled outside the United States during this fateful interlude. Thirty-eight (59%) had foreign-born sex partners. Among eight (12.5%) carrying major resistance mutations, seven traveled outside the United States during their exposure period and four had sex with foreign-born partners during that time. Six of these eight had NRTI-inspired mutations, three had NNRTI mutations, and two had protease inhibitor (PI) mutations.
Truong suggested that "HIV prevention strategies should incorporate specific counseling on risk of cross-border acquisition and transmission of drug-resistant HIV infection, particularly in an era of expanding antiretroviral treatment worldwide."
Rio offered an ample array of studies confirming that antiretrovirals don't stop working at the Tropic of Cancer, even though health-care setups in southern climes vary widely. In countries such as Brazil and South Africa, two conference reports showed, response rates have proved exemplary. Rio also confirmed good responses to reasonable regimens in less-heard-from regions. But so-so ART stews up North leave the same lukewarm taste down South.
Brazilian Generics Working Well
Brazil's universal antiretroviral program rests one foot on drug-company deals while planting the other on home-made generics. That stance looks solid -- even more so since 2000 -- according to a retrospective review of Brazilians starting their first antiretrovirals from 1996 through 2004 [abstract MoOa0204]. At the end of 2004, reported Mauro Schechter (Federal University of Rio de Janeiro), 140,000 Brazilians were taking antiretrovirals.
Schechter's virologic response analysis involved 485 adults (36% women) who took potent ART for at least six months and had baseline and six-month viral load readouts. Study participants came from two public health clinics, one clinical trials unit, and one private practice. Their ages averaged 38 years (+11 standard deviations [SD]) and they began their antiretroviral pilgrimage with a median viral load of 82,500 copies/mL and a median CD4 count of 185 cells/mm3 (+129 SD). More started with an NNRTI regimen (53%) than with a PI (44%), three NRTIs (2%) or a PI/NNRTI combo (2%).
As in other countries with clinical trial units, people enrolled in trials averted early virologic failure -- a viral load at or above 400 copies/mL after six to nine months -- more often than people in public clinics (Table 3). But Brazilians cared for in private practice did best of all, even though all three groups started with similar CD4 sums.
How Durable is ART in South Africa?
Six-month response, as in the just-reviewed study, can give a good feel for what lies down the road. But there's nothing like hard outcomes to gauge how smoothly an ART rollout is really rolling. Linda-Gail Bekker (Desmond Tutu HIV Center, Cape Town) opened a 24-month window on response in the Usapho Lwethu (Swahili for "Our Family Clinic") project (Figure 1), launched in September 2002 in a Cape Town district with a grim HIV prevalence of 29% [abstract MoPp0302].
So far Bekker and colleagues have screened 1,277 people and started treating 940 adults and 50 children. The group's age averaged 34 years and 76% are girls or women. Baseline CD4 count stood at 93 cells/mm3 and viral load at 100,000 copies/mL. Nine in 10 people beginning treatment had WHO Stage 3 or 4 HIV disease. Everyone started d4T/3TC plus nevirapine (NVP) or EFV.
Through 24 months of follow-up more than 90% saw their viral load drop under 400 copies/mL and stay there (Table 4). Most of these people had a viral load below 50 copies/mL. Adherence measured by pill count stood at or above 90% through 32 months of follow-up. After one year of treatment, 7.3% had died and only 3.3% stopped returning for visits. Only 0.9% needed a second-line regimen so far.
Universal Access Lifts Chile
Sitting astride the Andes on the verge of Brazil's vasty plain, Chile recently adopted its neighbor's universal antiretroviral access rule. And the strategy seems to be working there too, reported Carlos Beltrán and Marcelo Wolff (Chilean AIDS Study Group, Santiago) [abstracts MoOa0201 and MoPe11.6C21]. By the time the Chilean team arrived in Rio, about 6,000 people had HIV on the run thanks to ART.
Beltrán and Wolff detailed responses in 2,103 people, 85% men, starting their first antiretrovirals. The median age group had lived 35 to 39 years, and 47% had AIDS. A sizable majority, 84%, began with an AZT/3TC backbone, 44% with EFV, 29% with NVP, and 18% with indinavir (IDV).
After a median follow-up of 784 days, 143 people (6.8%) had died and 179 (8.5%) quit therapy. Beginning ART with a CD4 count under 100 cells/mm3 raised the risk of death 4.5 times. Among 1,781 people still taking antiretrovirals, three quarters continue their starting regimen.
At six, 12, and 24 months of treatment, 74%, 80%, and 80% respectively had a viral load below 400 copies/mL, while 66%, 72%, and 74% had fewer than 80 copies/mL. Virologic response did not differ by age, gender, or starting CD4 count. People with lower baseline loads responded faster, but this difference evaporated after 18 to 24 months of follow-up.
Boosted PI or Triple NRTIs in Africa?
Countries new to ART mirror countries with decades-long ART histories not only in response rates, but also in which regimens work better. European and US guideline writers consistently advise against first-line triple NRTIs because even the best of such regimens come up short when compared with NNRTI14 or boosted-PI medleys. Though they involve different populations, two Rio reports confirmed that NRTI threesomes lack some luster as first-line therapy while a ritonavir (RTV)-boosted PI puts tighter clamps on HIV.
The Developing AntiRetroviral Therapy in Africa (DART) trial in Uganda and Zimbabwe includes 2,468 people (74%) taking AZT/3TC (as Combivir) plus tenofovir (TDF) as their first antiretroviral regimen. Pontiano Kaleebu (MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda) spelled out 48-week results on 300 people in a retrospective virology substudy, including 100 from each of two Ugandan sites and 100 from the Zimbabwe cachement [abstract WeOaLB0203]. No one in DART gets real-time viral load measures.
Two thirds of the 300 substudy participants were women. Median baseline numbers were 100 cells/mm3, 279,901 copies/mL, and 37.3 years of age (range 20 to 62 years). After 48 weeks of followup, 38 people (13%) had stopped ART for three or more days, 17 (6%) traded AZT for d4T, and 231 (77%) continued their original regimen. Kaleebu did not account for the remaining 14.
At week 48, a missing-data-equal-failure analysis figured 65% with a viral load under 400 copies/mL and only 55% under 50 copies/mL. Respective on-treatment analysis rates were 74% and 62%. These mediocre responses match those in the AIDS Clinical Trials Group (ACTG) study comparing AZT/3TC/abacavir (ABC) (as Trizivir) with two EFV-based regimens14 and lag those seen, for example, with lopinavir (LPV)/RTV.15 After 48 weeks, 16% in DART had a viral load topping 10,000 copies/mL. These results appear to confirm the risk of starting with three NRTIs in people with a high viral load.
The NOGOMA study of RTV-boosted IDV does not offer a clean comparison with the DART trial because all study participants already had a good response to unboosted IDV three times daily [abstract MoPe11.7C08]. But these 48-week results laid out by Mamadou Cissé (CESAC, Bamako, Mali) confirm the power and sparky pharmacokinetics of twice-daily IDV/RTV at 400/100 mg twice daily and suggest that people without refrigerators can profit from the RTV kick.
Cissé tracked 18 women and 12 men who switched to IDV/RTV and kept the same NRTIs after getting their viral load below 400 copies/mL. All 30 showed they coped well with IDV by racking up two to 74 months of experience. Yet the median IDV trough measured only 191 ng/mL and ranged from a perilous 12 ng/mL to 425 ng/mL. After switching to IDV/RTV, 62% kept their RTV refrigerated while 21% relied on a thermos and 17% on traditional jars. Cissé figured that about half the people in the CESAC program have refrigerators.
After 48 months of RTV-buoyed therapy, 28 of 30 people had a viral load under 400 copies/mL and 25 had fewer than 50 copies/mL. One of the two people who had an RNA reading above 400 copies/mL dropped below that mark after stopping antacids. The second person had a rebound after stopping all antiretrovirals during a bout of malaria. Her viral load fell below 400 copies/mL when she resumed treatment. One person couldn't stomach RTV and returned to thrice-daily IDV with no loss of viral control.
Switching from unboosted to boosted IDV hoisted the IDV trough from 191 ng/mL at baseline to 455 ng/mL at week four (P < 0.001), where it stayed through 48 weeks. Defining an adequate IDV trough as 150 ng/mL, Cissé counted 64% at that level when starting IDV/RTV, 89% at week four (P = 0.11), and 96% at week 48 (P = 0.02). People with a fridge at home did no better than those without in RNA response or IDV trough (Table 5).
Who Follows WHO Guidelines?
All 36 poor or developing countries responding to a WHO questionnaire about antiretroviral guidelines said they heeded WHO advice on when to start ART [abstract MoPeLB11.10C01]. But agreement with WHO fell off considerably on other questions, reported the organization's Eddy Beck.
Thirty-six of 43 WHO "3 x 5" countries (84%) sent back completed questionnaires. With a scoring system developed to test national concordance with the WHO's 2003 document entitled Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach, Beck charted the following median rates of agreement:
Median concordance for all 26 questions stood at 65 (IQR 56 to 76). Countries that revamped their guidelines since WHO published its 2003 advice had a nonsignificantly higher overall median concordance (71 versus 56, P = 0.176). And African countries hewed closer to WHO counsel than other nations (68 versus 59, P = 0.243).
Sixteen respondents (44%) based ART intervention on WHO clinical staging criteria and CD4 or total lymphocyte count, 12 (33%) used clinical staging and CD4 criteria, and four (11%) used clinical criteria alone. Thirty-one of 36 respondents (86%) felt viral load testing has no place in figuring whether to start ART. Thirty-three countries (92%) specified a favored first-line regimen, 24 of them (66%) opting for d4T, 3TC, and NVP. Thirty-three countries also listed a preferred back-up combination, 24 of them picking ddI, ABC, and LPV/RTV.
Although all respondents had clear opinions on most antiretroviral questions, only three (8%) had formal guidelines and none had published guidelines.
Probably the biggest antiretroviral news from Rio headlined TDF plus emtricitabine (FTC) as a better first-line option than tried, true, but maybe tired AZT/3TC. The conference also offered a raft of other reports on thymidine versus nonthymidine analogs, more data on intensifying therapy, three looks at a single solo-PI maintenance study, and a growth industry of research on growth hormone.
New bone cells replace old ones all the time, but by and large we're pretty much stuck with the same bones we're born with. And as time wears on, those bones wear out. The spine that keeps us bipedal does a much better job in our 20s than our 80s.
Not so with NRTI backbones. These regimen ridgepoles just keep getting better. AZT/ddI, the coelacanth of nuke backbones, turned out to swim more smoothly than an evolutionary array of descendants, such as AZT/zalcitabine (ddC) and ddI/d4T. But AZT/3TC emerged as the standard spinal model, especially when fused in a single twice-daily pill.
Rio's richest antiretroviral news came in a report showing the sterner mettle of this century's new leading backbone contender, TDF/FTC, now bonded in a single once-daily pill (Truvada) [abstract WeOa0202]. Anton Pozniak (Chelsea and Westminster Hospital, London) spoke for a multicenter team that pitted TDF/FTC (taken once daily as separate pills) against AZT/3TC (taken twice daily as Combivir) in 509 people also starting EFV in their first antiretroviral regimen. A 48-week analysis of this ongoing 144-week trial found TDF/FTC significantly superior on virologic, immunologic, and most toxicologic grounds.
The well-matched study groups both had median viral loads around 100,000 copies/mL and 41% with CD4 counts under 200 cells/mm3. Using the US Food and Drug Administration's pet benchmark -- time to loss of virologic failure from under 400 copies/mL -- Pozniak figured an 81% intent-to-treat response rate with TDF/FTC versus 70% with AZT/3TC (P = 0.005) after 48 weeks. TDF/FTC also beat AZT/3TC in an intent-to-treat sub-50-copy contest, 77% to 68% (P = 0.034). Although statisticians framed the study to prove TDF/FTC's "noninferiority" to AZT/3TC, Pozniak noted, the CIs around these differences apparently certify TDF/FTC's superiority.
Among people with confirmed rebounds above 400 copies/mL, genotypers saw more mutant virus in the AZT/3TC group:
People taking TDF/FTC gained an average 190 cells/mm3 compared with 158 cells/mm3 in the AZT/3TC group, a statistically significant (P = 0.002) though perhaps not clinically cogent difference.
Tenofovir/FTC proved significantly more tolerable than AZT/3TC: While 4% stopped TDF/FTC because of side effects, 9% shelved AZT/3TC (P = 0.016). Ten people (4%) taking TDF/FTC complained of some side effect, compared with 23 (9%) on AZT/3TC. Anemia proved the biggest problem with AZT/3TC, affecting 14 people (6%) in the AZT/3TC group and no one taking TDF/FTC.
In the kidney department, no one taking TDF/FTC saw their serum creatinine climb through week 48. While glomerular filtration slowed nonsignificantly by 1.3 mL/min with TDF/FTC, it rose 6.2 mL/min (P < 0.001) with AZT/3TC.
Lipid and fat trends appeared to favor TDF/FTC through 48 weeks of treatment:
So is TDF/FTC the best backbone going? It's surely better than AZT/3TC in treatment-naive people for 48 weeks. But whether it betters -- or measures up to -- another once-daily option, 3TC/ABC, remains to be tested. And so far attempts to blend TDF/FTC with EFV in a single once-a-day potion have come up short, but Gilead Sciences will keep trying.
Thymidines Versus Nonthymidines
The just-reviewed NRTI results are the latest volley in a research fusillade aimed at answering one question: Should first-line NRTI backbones include or exclude a thymidine nucleoside analog? These days, that question usually means should the backbone include or exclude AZT, since no one with a choice prescribes d4T up front.
Avoiding thymidine analogs in treatment-naive people gained currency a few years back when resistance experts learned that TAMs made HIV less susceptible to nonthymidine analogs as well. And though d4T does more toxic damage than AZT, both drugs have ineluctable short- and long-term side effects. Dogged resistance paladins also showed that some mutants evoked by nonthymidine analogs (K65R by TDF and L74V by ddI) are hypersusceptible to the thymidine analog AZT16 -- facts one might cite to argue for sequencing nonthymidines first. But one highly touted nonthymidine combo, ddI/TDF, floundered in important tests.
Maybe what's really needed is a thymidine analog less toxic than either current option. But none seems near the pharmacy shelf. So clinical researchers still spend lots of time sorting the merits and demerits of thymidines and nonthymidines.
Naa Torshie Annan (Chelsea and Westminster Hospital, London) cast an intriguing retrospective look at 723 treatment-naive people starting EFV and 271 starting NVP with two NRTIs [abstract WePe12.2C03]. The Chelsea and Westminster team mounted this study to disentwine potential confounders in cohort analyses comparing the two NNRTIs (which favored EFV) and the randomized 2NN study17 (which saw no difference). An analysis adjusted for such confounders and stratified by year, viral load, and NRTI backbone found a 27% lower likelihood of virologic success (But, 2NN or no 2NN, most prescribers probably favor EFV at this pass, so the study's more valuable findings may involve backbone differences. A plurality of enrollees, 48%, started with AZT/3TC, while the next most popular spinal specimens were ddI/d4T in 13% and d4T/3TC in 12%. Picking the popular AZT/3TC duo as the comparison backbone (relative hazard [RH] 1.0), Annan found a significantly better chance of virologic success with the thymidine-containing d4T/3TC and a significantly lower chance with nonthymidine mixes:
On top of that, the now-notorious nonthymidine pairing of ddI/TDF proved the only significant predictor of treatment failure. Compared with AZT/3TC, ddI/TDF made failure 6.48 times more likely (95% CI 3.81 to 11.0) (P < 0.001).
Of course cohort studies have their own blind spots because they lack randomization. Chelsea and Westminster physicians clearly lean toward EFV, prescribing it almost three times more often than NVP. Yet the proportion of women starting NVP significantly exceeded the proportion of men (P < 0.001). And the NVP group began treatment with a significantly lower viral load (P < 0.001) and a higher CD4 count (P = 0.054).
Three Chelsea and Westminster physicians published a nice exegesis of the ddI/TDF saga just after the conference,18 concluding that this dyad's convenience and relative safety vanish in the pitchy shadow of CD4 depletion and a high virologic failure rate when combined up front with NNRTIs. Tenofovir/ddI may be a better bet with RTV-boosted PIs and in people with treatment experience, they suggest, but they cite cohort data documenting pancreatic toxicity and high glucose in people taking such regimens.19,20
A cohort study posted in Rio concurred that ddI/TDF looks reasonable when linked to a PI, especially in simplification regimens [abstract WePe12.9C07]. But which PI you use may make a difference.
M. Olmo (Hospital de Bellvitge, Barcelona) and colleagues in three other Spanish hospitals studied 517 people starting ddI/TDF from January 2002 through June 2004. Only 33 were treatment-naive, while 163 had an undetectable viral load with another regimen and switched to ddI/TDF to make pill taking simpler. Another 148 people made ddI/TDF part of a first or second rescue regimen, and 173 took the NRTIs as part of a third or later rescue combo.
In simplifying regimens ddI/TDF performed equally well with a PI or an NNRTI (Table 6). But PIs handily outdid NNRTIs with ddI/TDF in starting and rescue regimens. Whereas 8.7% taking ddI/TDF with LPV/RTV in rescue regimens experienced virologic failure, 28% with another PI as the third rescue drug suffered failure (P = 0.002). The other PIs most often used were atazanavir (ATV)/RTV in 16, nelfinavir (NFV) in eight, saquinavir (SQV)/RTV in five, and IDV/RTV in four.
A Cox proportional hazards model figured a higher risk of ddI/TDF failure when the third drug was an NNRTI or NRTI rather than a PI, when physicians did not lower the ddI dose, and when they used the drugs in up-front or rescue regimens rather than to simplify suppressive combinations:
Picking up TAMs with a first regimen lowered the chance of second-line success in a single-center retrospective study of 97 people by Franco Maggiolo (General Hospital, Bergamo, Italy) [abstract WePe4.4C09]. But in a multivariate analysis, using a thymidine analog in the first regimen did not dim prospects for successful rescue therapy.
These 97 people, 64% of whom acquired HIV heterosexually, had a mean CD4 count of 314 cells/mm3 and a mean viral load of 16,714 copies/mL when their first antiretrovirals pooped out. Maggiolo did not report the numbers taking a first-line thymidine analog, PI, or NNRTI. But all were taking purportedly potent regimens.
Defining second-line response as a viral load below 400 copies/mL six months after starting a new regimen, Maggiolo reckoned a failure rate of 61.5% in people with TAMs versus 33.8% in the TAM-less (P = 0.02). Whereas 66.2% without TAMs from their first regimen had success with their second, only 38.5% with TAMs notched a sub-400-copy viral load the second time around.
But a multivariate analysis sequestered no independent predictors of second-line success, including use of a thymidine analog or any other antiretrovirals in the inaugural concoction. Nor did the TAM pattern (mutations at codons 41, 210, and 215 versus 67, 70, and 219 versus mixed patterns) help separate second-line responders from nonresponders.
In another study, Maggiolo eyed three once-a-day nonthymidine duos plus EFV as first-time regimens [abstract WePe12.2C04]. This multicenter open-label trial randomized 72 people to start ddI/3TC, 64 3TC/TDF, and 63 ddI/ABC plus the once-daily NNRTI. These people had fairly advanced disease, with baseline viral loads and CD4 counts of 228,783 copies/mL and 172 cells/mm3 in the ddI/3TC group, 211,185 copies/mL and 203 cells/mm3 in the 3TC/TDF group, and 193,326 copies/mL and 183 cells/mm3 in the ddI/ABC group.
A 24-week interim analysis hinted at a better virologic response to the oldest NRTI options assessed, ddI plus 3TC (Table 7). But Maggiolo and colleagues did not compare these outcomes statistically. Substantially more people stopped ddI/ABC (18%) than ddI/3TC (11%) or 3TC/TDF (10%). CD4 count gains averaged 350 cells/mm3 in every treatment arm.
Lower Risk of Liver-Related Death With Earlier HAART?
HIV clinicians in developed countries needn't be told that liver disease now stalks antiretroviral-treated people as a leading death threat. This shift reflects not the hepatotoxic potential of some antiretrovirals, but control of traditional opportunists and the spectral coincidence of the HIV and hepatitis virus epidemics. Yet liver failure counts as a "non-AIDS death." Massimo Puoti (University of Brescia, Italy) came to Rio with evidence that starting antiretrovirals earlier lowers the risk of liver failure and other non-AIDS deaths [abstract WePe12.2C29].
Puoti tracked mortality in 809 members of his Brescia cohort, defining non-AIDS death as death without a major opportunistic infection or cancer. Through three years of follow-up he counted 91 such deaths, about half due to liver disease. Nearly one third of all deaths could not be tied to AIDS.
A multivariate model determined that a single risk factor for liver injury independently raised the odds of non-AIDS mortality 2.87 times (P = 0.0052). Having two or more liver injury risks boosted non-AIDS mortality 4.83 times (P < 0.0001).
Taking potent antiretrovirals lowered the risk of dying without AIDS 56% (P = 0.0016). Compared with starting treatment at a CD4 count under 200 cells/mm3, starting with 201 to 349 cells/mm3 trimmed the non-AIDS death risk 10%, a nonsignificant improvement (P = 0.39). Starting antiretrovirals with more than 350 cells/mm3 made a non-AIDS death 15% less likely (P = 0.03) -- independent of liver disease.
Even if antiretroviral-induced toxicity poses stern challenges in managing HIV disease, Puoti concluded, starting treatment before CD4 tallies sink below 350 cells/mm3 apparently makes liver-related and other non-AIDS deaths less -- not more -- likely.
Intensifying and Disintensifying
Two perdurable questions about antiretroviral strategizing still lack good answers: When should you intensify a less-than-ideal regimen? And when can you disintensify a good one, opting for simpler maintenance therapy instead?
Kimberly Smith (Rush Presbyterian Medical Center, Chicago) and US AIDS Clinical Trials Group (ACTG) mates faced up to the first question in a 48-week trial of add-on TDF plus a PI switch to LPV/RTV [abstract WePe16.7B06]. The earlier ACTG protocol 375 showed that even long-term viral control below the 100-copy mark does not correct faulty responses to antigens, completely defuse frenzied immune cells, or hoist CD4 counts into normal domains. So Smith and colleagues planned protocol A5136 to see if intensifying an already-good regimen would restore immunologic order.
All 17 study participants had a viral load below 1,000 copies/mL on a PI regimen started during ACTG 315. To ratchet up antiviral vim, Smith added the nucleotide RT inhibitor TDF and switched everyone's PI to LPV/RTV. Seven of these 17 people had at least one RNA reading above 100 copies/mL during 48 weeks of follow-up, while 10 kept their viral load under 50 copies/mL -- and six ended up with fewer than 10 copies/mL.
These 10 responders started their first PI with a median CD4 count of 190 cells/mm3 (range 121 to 233 cells/mm3) and a median load of 89,798 copies/mL (range 39,192 to 265,330 copies/mL). Before intensification their CD4 counts ranged from 405 to 774 cells/mm3 and all had a sub-50 viral load.
During 48 weeks of intensification the median CD4 count of the 10 sub-50 responders edged up from 553 to 584 cells/mm3, a significant change (P = 0.0078) that may have less clinical significance. This CD4 gain reflected a jump in memory T cells, as naive T lymphocytes trickled away. Smith speculated that a tired thymus failed to mint fresh CD4 cells in these long-infected people.
CD4 percent, CD8 count, and CD8 percent changed little after shifting to LPV/RTV and adding TDF. In nine people tested, apoptosis dropped significantly. Intensified therapy did nothing to drain latent T-cell reservoirs.
Smith concluded that intensified therapy in people with long-term viral control "may lead to improvements in total CD4 lymphocyte recovery primarily via restoration of memory cells." But it's important to remember that only 10 of 17 people (59%) even kept HIV under wraps after supposedly bucking up their regimen.
Boosted PI monotherapy has surfaced as a favored maintenance tactic for venturesome trialists, though its rationale remains dubious. Why levy all your antiretroviral might against a single target with relatively toxic drugs, when you can shred two viral targets with convenient, comestible EFV/NRTI combos? Does a burning need to improve therapy lie behind these trials? The honest answer must be no.
Research so far suggests two reasons why mono-PI maintenance doesn't measure up:
The first dictum held true with ATV/RTV monotherapy in a study by Pietro Vernazza (Cantonal Hospital, St. Galen, Switzerland) [abstract WeOa0204], who earlier studied IDV/RTV monomaintenance, partly because of IDV's brain-breaching and semen-sating repute.21 The pilot IDV/RTV trial involved 12 people who kept their plasma load below 50 copies/mL for at least three months with boosted IDV and two NRTIs -- then stopped the NRTIs. Central nervous system (CNS) T-cell lymphoma struck one person, who committed suicide 32 weeks after scaling back his regimen; the other 11 maintained sub-50 loads through a median 78 weeks of follow-up, despite occasional blips.
Vernazza made "special efforts" to keep adherence high and checked IDV levels for hints of toxicity. Still, four people paid the price of continuing IDV/RTV with renal toxicity, including three kidney stone bouts and two cases of creeping creatinine. Dropping NRTIs for 48 weeks did not improve DEXA-checked fat abnormalities. Despite the CNS-and-semen rationale for using IDV, Vernazza did not list spinal fluid or seminal HIV loads in his report on this trial.
But he did relay CNS and seminal findings in his Rio report on ATV/RTV, and the news wasn't great. As in the IDV/RTV trial,21 everyone in this study had kept HIV in check below the 50-copy mark with a traditional regimen (for a median 9.4 months), and none had a treatment failure on their chart. Everyone started ATV/RTV (300/100 mg daily) and stopped their NRTIs.
Among 24 people who finished 24 weeks of boosted monotherapy, Vernazza counted two failures: One person dropped out at week 20, and one had an outright virologic failure at week 8. This second person then confessed failure of an earlier regimen -- a protocol violation. Of course in routine practice, more than one person may blur the truth about earlier failures if they want to try something that looks easier.
Of 15 seminal samples checked before monotherapy, two had an RNA load topping 100 copies/mL. Two of 12 checked at week 24 still had detectable RNA in semen. Two of five cerebrospinal fluid samples audited at baseline had RNA readings above 100 copies/mL, as did two of 12 checked at week 24. So it seems ATV/RTV has a tough time scouring HIV from semen and spine fluid.
Vernazza didn't randomize his IDV/RTV or ATV/RTV trials, but José Arribas (La Paz Hospital, Madrid) did mount a random comparison of LPV/RTV maintenance therapy and continued triple therapy in the so-called OK Study of 42 people with viral loads under 50 copies/mL for more than six months and no PI failures in their record [abstract WePe12.3C05 and WePe12.3C06]. Monomaintenance didn't work for four people, but continued triple therapy permitted no viral breakthroughs.
The maintenance group started the trial with two statistically nonsignificant advantages:
After 48 weeks of follow-up, Arribas tallied three virologic failures (two loads above 500 copies/mL) in the LPV/RTV monomaintenance group and none with steady triple therapy. One person dropped out of the maintenance arm with a detectable load attributed to poor adherence (and more on this below), while high lipids knocked one person out of the three-drug control group.
Those numbers translated into intent-to-treat success rates of 81% with LPV/RTV maintenance and 95% with standard therapy. Three other people in the LPV/RTV mono arm blipped above 50 copies/mL, compared with one in the control group. Primary PI mutations did not pop up during rebounds or blips, and all rebounders reharnessed HIV after resuming their NRTIs.
Probably because PIs are the prime culprits in out-of-line lipids, stopping NRTIs did nothing to improve lipid profiles in this study. The two study groups had no significant lipid changes or differences 48 weeks after randomization.
Analyzing reasons for virologic failure in this trial, Federico Pulido (Doce de Octubre Hospital, Madrid) found two -- briefer viral control before randomization and (surprise!) shaky adherence. The four people with viral breakthroughs on solitary LPV/RTV spent a median 40 weeks (IQR 30 to 84 weeks) under 50 copies/mL before randomization, compared with 132 weeks (IQR 40 to 331 weeks) in the constant suppressors (P = 0.02).
Adherence findings, based partly on the GEEMA adherence questionnaire22 and partly on prescription refills, undermine contentions that people find it easier taking one drug than taking three. The 17 people with steady sub-50 control had a median zero days without medication during the trial, compared with three days in the rebounders (P = 0.008). Median missed doses in the week before a clinic visit measured zero in the constant responders and three in the breakthrough group (P = 0.013).
Pulido also saw a marked trend toward better adherence by drug refill score in the steadily suppressed group (94% versus 70%, P = 0.14). Three of the four people with breakthrough viremia had refill scores of 59%, 60%, and 70%. Scaling back to a one-drug regimen apparently made these people more forgetful or more reckless. The fourth person whose RNA rebounded during monotherapy had perfect adherence by this score -- a finding that either shows the limits of refill scores or suggests some still-undiscovered reason for that rebound.
Rather than featuring these insightful analyses in a slide session, the Rio conference's science panel elected to favor yet a third look at this trial, perhaps the least important of the three. Using a rejiggered Roche Laboratories assay that can spot three RNA copies/mL, John McKinnon (University of Pittsburgh) retested plasma samples from the LPV/RTV mono and control arms [abstract WeOa0203]. Median loads reckoned with this test didn't differ between study groups at any point in the trial, but the four people with viral breakthroughs certainly tugged up their group's median. In these four McKinnon picked up the first hints of recrudescing RNA eight weeks after randomization, a sibylline bubble that popped above the 50-copy surface around week 32.
Physicians who run these studies always close by warning against mono-maintenance in practice. And one hopes the array of risks portrayed in these results will temper enthusiasm for this tactic. Yet reports on boosted PI monotherapy almost always accentuate the positive -- and rarely the negative. But one could argue the negatives matter more when testing a risky -- and perhaps gratuitous -- strategy.
CD4 Spurts With Growth Hormone
Recombinant growth hormone did great as a remedy for AIDS wasting, but it always received mixed marks as a tonic for truncal fat: the hunt is still on for a tolerable long-term dose. But three reports in Rio thrust growth hormone into a new role -- a CD4 booster that may prick up HIV-specific immune responses.
Two years ago Mike McCune's Gladstone Institute team showed in a pilot study that six to 12 months of growth hormone reversed thymic shrinkage in five HIV-infected adults and inflated quotients of critical naive CD4 cells.23 The same researchers, an ACTG troupe, and a London team offered results of bigger, randomized trials at the Rio conference, and the returns remained positive.
The ACTG effort randomized 55 men and five women to add 1.5 mg of recombinant growth hormone daily to their antiretrovirals for 48 weeks or to continue antiretrovirals for 24 weeks and then add 3 mg of growth hormone daily for the next 24. Everyone had tight viral control with sub-50-copy viremia for more than one year. Study participants started the trial with a mean CD4 count of 230 cells/mm3 (IQR 161 to 300 cells/mm3). Median age was 47 years in the 1.5-mg arm and 48 years in the 3-mg arm.
Rush Presbyterian Medical Center's Kimberly Smith reported that eight people stopped growth hormone before the study ended, six of them (10% overall) because of carpal tunnel syndrome and two for reasons unrelated to the drug [abstract TuOa0203]. Grade 3 or 4 side effects cropped up in seven people taking 3 mg and four taking 1.5 mg, while seven in the 1.5-mg group and five in the 3-mg group had grade 3 or 4 lab skews (including three triglyceride jumps with 1.5 mg).
The 1.5-mg dose started adding naive and total CD4 cells right away, while little changed in the 3-mg delayed-treatment group (Table 8). Then, when the 3-mg group started growth hormone at week 24, it caught up with the 1.5-mg arm in CD4 gains. A CT scan substudy showed a growing thymus in seven of 11 people taking 1.5 mg (P = 0.06) and seven of nine taking 3 mg (P = 0.016) for 24 weeks.
Laura Napolitano (Gladstone Institute, San Francisco) devised a more complex trial scheme, randomizing 10 adults (group 1) to 3 mg of growth hormone for six months then 1.5 mg for another six months, and nine people (group 2) to one year of observation without growth hormone [MoPpLB0104]. In the second year, the untreated group injected 3 mg of growth hormone for six months and 1.5 mg for another six while the already treated people became untreated controls. Her Rio report covered year-1 results.
Group 1 was slightly older (median 54 versus 48 years, P = 0.49) and had a marginally higher CD4 count (median 230 versus 178 cells/mm3, P = 0.21). The groups matched exactly in median time on stable antiretroviral therapy (2.7 years), median viral load (75 copies/mL), and median thymus score (1.0).
In the study's first year, thymus score, density, and volume all burgeoned in the treated group but stayed flat or shrunk in untreated controls. The thymus score climbed 1.51 with growth hormone and dropped 0.02 without it (P = 0.004). These findings mirror results in the ACTG trial. Total CD4 cells rose 19% with growth hormone (P = 0.093) and naive CD4s 69% (P = 0.0002) with growth hormone, but naive CD8 cells did not. Napolitano suggested the discrepancy between naive CD4 and CD8 gains could mean some CD8s may have a font outside the thymus.
Side effects proved even more problematic in this trial than in the ACTG study, perhaps because everyone started with 3 mg daily. Four of 10 people gave up on growth hormone -- one with diabetes diagnosed after one month, one with carpal tunnel syndrome after six months, one with fatigue after seven months, and one with hand pain after nine months. On top of that, six people temporarily suspended treatment or stepped down to the lower dose early because of glucose intolerance, arthralgias, or carpal tunnel syndrome.
In a third trial, Nesrina Imami (Imperial College, London) and colleagues at Chelsea and Westminster Hospital gave 4 mg of growth hormone daily for 12 weeks to 12 people with a CD4 count above 200 cells/mm3 and well-controlled viremia [abstract WePe16.7B01]. For the next 12 weeks they got evenly randomized to placebo, 4 mg every other day, or 4 mg twice weekly.
Proliferative CD4-cell responses and levels of interferon-γ-producing CD8 cells rose significantly during the 12 weeks of daily therapy. Before growth hormone therapy only one of 12 study participants had evidence of HIV-specific CD4 responses. Nine achieved such responses after 12 weeks of daily therapy (P < 0.05), but HIV responses waned with less frequent dosing. Two assays verified significant gains in CD8 cells secreting interferon-γ during daily growth hormone therapy, and those gains lasted through week 24 in all three study arms. By week 48, these markers of immune response had begun fading.
Despite this trial's 4-mg dose, no one had growth hormone-related side effects and no one dropped out.
Important questions remain about using growth hormone to pluck up CD4 and CD8 responses to HIV:
The London study hints that the answer to the fourth question is no.
Reviving the thymus with growth hormone may make sense not only because this butterfly-shaped clump of lymphoid tissue flutters more fretfully with age, but also because antiretrovirals may send it into tailspin. Checking patient records and running thymus scans told P. Sen (Chelsea and Westminster Hospital, London) that rates of both hypo- and hyperthyroidism soared after potent therapies arrived, apparently thanks to NNRTIs in the first case and to PIs in the second [abstract TuPe2.3C09].
First the Chelsea and Westminster team parsed files of everyone in the HIV clinic treated with thyroid meds between April 1995 and June 2004. They turned up 25 cases of hypothyroidism and eight cases of hyperthyroidism in people with a median CD4 count of 228 cells/mm3 (IQR 156 to 325 cells/mm3). Diagnosis of hypothyroidism jumped 10-fold in the potent antiretroviral era, while hyperthyroidism incidence ballooned 8.5-fold (Table 9).
CD4 count did not correlate with a sputtering thymus in these analyses. Sen and colleagues believe their findings justify routine thyroid function testing for people taking antiretrovirals, especially PIs or NNRTIs.
Mark Mascolini writes about HIV infection (firstname.lastname@example.org).
Acknowledgment: Thanks to Alan MacRobert, Senior Editor of Sky & Telescope, for his deft explanation of why night falls fast in the tropics. See note 1.
Editor's Note: See the December 2005 issue of the IAPAC Monthly for Part 2 of this article, which will analyze news on second-line regimens, treatment interruptions, antiretroviral toxicities, and HIV-related coinfections.
This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.