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Dear Readers,
Every winter, when the editors of AIDS Clinical Care look back over 12 months of HIV clinical care and research to choose our top stories, we see that there have been some startling advances — and notable disappointments. We’re often surprised to discover that the findings we’ve come to think of as old news were really reported only within the past year, but such is the fast-moving nature of this field. Below are the Top HIV/AIDS Stories of 2007, grouped loosely by themes.
We’ve known since the late 1990s that the most successful antiviral regimens contain at least two fully active drugs. However, our ability to construct such regimens has been limited by extensive cross-resistance within drug classes, leading to extensive reshuffling and recycling of agents, not surprisingly with little chance of achieving virologic suppression. A common strategy for managing patients with virus resistant to all three major drug classes has been to keep them on “failing” regimens, awaiting the availability of new agents.
Wait no more: This year’s FDA approval of maraviroc and raltegravir marked the first new orally bioavailable drug classes introduced for HIV treatment since 1996. When used with optimized background regimens in patients with highly drug-resistant HIV, maraviroc and raltegravir have both been shown to yield virologic suppression rates comparable to those achieved with initial treatment regimens during the late 1990s (ACC Apr 2 2007).
All is not perfect with these drugs, however. Patients considering maraviroc must first undergo testing with a cumbersome and very expensive viral tropism assay (list price, nearly US$2000). The test might miss low levels of dual/mixed-tropic virus, results take 3 to 4 weeks, and, because of its cost, the test is not universally covered by payors. In addition, only about half of all highly treatment-experienced patients will have R5-tropic virus and hence be appropriate candidates for the drug. With raltegravir, nonsuppressive regimens quickly lead to the development of raltegravir resistance mutations, which seem to generate cross-resistance to elvitegravir, the other integrase inhibitor in development (ACC Jul 9 2007). From the resistance perspective then, integrase inhibitors are like other antivirals — optimally used only in combination with another fully active agent, to maximize the chance of a durable response. The importance of this approach is further underscored by the relative lack of new drugs in development: After the expected approval of etravirine — the novel NNRTI with activity against some NNRTI-resistant virus (ACC Jul 30 2007) — in early 2008, there will literally be no antiretrovirals from novel drug classes in phase III studies.
Darunavir gained broad attention after the (oft-reported) POWER studies demonstrated its impressive activity against virus that is highly resistant to other PIs (ACC Apr 9 2007). Two subsequent studies indicated that darunavir will likely have a role throughout the spectrum of HIV disease. In the TITAN studies, treatment-experienced patients who had never received lopinavir/ritonavir received either ritonavir-boosted darunavir or lopinavir/r, along with an optimized background regimen. Results favored the darunavir arm overall and in all subgroups except those with no PI resistance at baseline (ACC Jul 23 2007). More recently, in the ARTEMIS study, treatment-naive patients were assigned to receive tenofovir/FTC plus either lopinavir/r or ritonavir-boosted darunavir at a novel dose that is not FDA approved: 800 mg of darunavir, plus 100 mg of ritonavir, both once daily (ACC Oct 5 2007). The overall results slightly favored darunavir, especially in patients who started the study with viral loads ≥100,000 copies/mL. Notably, this study set a new standard for what is achievable with boosted PIs as initial therapy: By week 48, 84% of patients in the darunavir group had achieved viral loads <50 copies/mL, which only slightly exceeded the also-excellent 78% response to lopinavir/r, a nonsignificant difference.
In addition to such positive reports on new drugs, helpful information also emerged for prescribing older agents, in particular, abacavir. This drug is highly effective and usually well tolerated, but its use has been limited by the potential for hypersensitivity reaction (HSR), which can be severe enough to require hospitalization and can even be fatal. In the elegantly simple PREDICT study, patients about to initiate abacavir were randomized as to whether or not to undergo baseline testing for human leukocyte antigen (HLA) B*5701 (ACC Sep 10 2007). Those who underwent screening were allowed to start abacavir therapy only if they tested negative for the allele; those who did not undergo screening started abacavir immediately and provided blood samples for later HLA typing. The results were clear: Pretreatment testing for 5701 halved the incidence of suspected abacavir HSR, and — most importantly — all the cases of immunologically confirmed HSR (defined by an investigational skin-patch test) occurred in patients who later tested positive for the allele. These results suggest that many (if not all) of the cases of suspected HSR that occurred in patients who later tested negative for 5701 were, in fact, overcalls, a suggestion further supported by the general absence of systemic symptoms in these cases. Not surprisingly, the use of HLA-B*5701 testing before initiation of abacavir therapy has rapidly become the standard of care in many settings and has been endorsed in the most recent treatment guidelines from the U.S. Department of Health and Human Services (DHHS; ACC Dec 10 2007).
Given the overall recent improvements in the safety, efficacy, and tolerability of initial antiretroviral therapy (ART), the pendulum has been swinging back in favor of earlier treatment initiation in asymptomatic patients. Perhaps the best data supporting this strategy come from a subset of patients in the SMART study who were treatment naive at enrollment and therefore provide a hint about what we might expect from a clinical trial addressing “when to start” (ACC Sep 10 2007). Individuals who delayed starting therapy until their CD4 counts were <250 cells/mm3 had significantly higher risk for opportunistic disease and non-AIDS illness than did those who received immediate treatment (median CD4 count, 435 cells/mm3). Based on these results and similar observations from cohort studies, the DHHS guidelines were recently revised to suggest that ART be started in asymptomatic individuals when the CD4 count falls below 350 cells/mm3 (ACC Dec 10 2007).
Of the various interventions tested to prevent HIV infection, male circumcision is the most strongly supported by evidence: In sub-Saharan Africa, circumcision has been confirmed to halve the risk for HIV acquisition (ACC Mar 19 2007). Questions about implementing this strategy abound, however, in terms of safety, patient acceptability, scale-up, and applicability to other populations (such as men who have sex with men) and to other parts of the world. In addition, we do not yet know the effect, if any, that male circumcision will have on transmission of HIV to others.
Unfortunately, the encouraging news about circumcision this year was countered by disappointing data from both microbicide and vaccine trials. Investigators halted a study of cellulose sulfate after observing a higher rate of seroconversions in women who used the microbicide than in those who used placebo (ACC Feb 12 2007). Because this study is the second one to suggest potential increased risk with microbicides (the first involved nonoxynol-9 [ACC Mar 1 2001]), researchers are now questioning whether any nonspecific microbicide can work in preventing HIV infection. Various antiretroviral agents are being evaluated for this purpose.
On the vaccine front, researchers have been focusing for several years now on the development of vaccines that elicit cellular immunity — in particular, HIV-specific cytotoxic T-cell response — rather than humoral immunity. The hope was that even if HIV infection could not be prevented completely, individuals who acquired HIV after vaccination might have a lower viral set point, potentially slowing disease progression and reducing the risk for transmission to others (ACC Jan 1 2004).
No such luck: In the international STEP trial, the adenovirus serotype 5 (Ad5) vaccine, which contained three HIV antigens, neither prevented infection nor lowered viral set point (ACC Oct 1 2007). Disturbingly, among individuals with high levels of preexisting immunity to Ad5, vaccine recipients appeared to be at higher risk for HIV acquisition than did placebo recipients, with a more than twofold increased incidence of infection (ACC Nov 19 2007). These results led investigators to immediately stop vaccinations in the study, and another large trial of an Ad5 vaccine is also on hold. As researchers struggle to explain the apparent increase in infection, a number of questions arise for future vaccine studies. What are the best candidates? How can safety be ensured? What are the right correlates of protection? Suffice to say that the results of this study were a huge blow to the HIV vaccine research effort and may well make recruiting for upcoming vaccines studies a formidable challenge.
More than a year has passed since the CDC first recommended that HIV screening be part of routine medical care in all healthcare settings, that an opt-out approach be used when offering testing, and that extensive pretest counseling need not be required (ACC Oct 6 2006). The main goal of these recommendations is to increase the number of HIV-infected people who are aware of their infection, thereby bringing them into care for treatment and enabling them to limit behaviors that might spread HIV to others. As noted in several studies, however, incorporating these guidelines can be a challenge, given existing state-by-state regulations (ACC Nov 5 2007). An encouraging finding came from San Francisco, where removing the need for written informed consent improved HIV testing rates and case identification (ACC Mar 26 2007). However, several other studies showed just how much still needs to be accomplished: In Baltimore, the median CD4 count among patients initiating HIV care fell from 371 cells/mm3 in 1990–1994 to 276 cells/mm3 in 2003–2006 (ACC Nov 5 2007); in the southern U.S., nearly half of all patients at a university HIV clinic had AIDS at the time of their HIV diagnoses in 2002–2004 (ACC Apr 30 2007); and in developed countries overall, the CD4 count at treatment initiation has been stable at 150 to 200 cells/mm3 since the year 2000 (ACC Apr 2 2007).
Accurate estimates of the scope of the HIV epidemic are necessary for designing programs and allocating resources. To that end, both global and national estimates are being readjusted as a result of changes in reporting and methodology. Worldwide, UNAIDS and the WHO have revised the estimated number of people living with HIV infection downward, from 39.5 million in 2006 to 33.2 million in 2007. In contrast, the CDC is expected to soon revise its estimates of HIV incidence in the U.S. upward. Since 1992, the CDC has estimated that approximately 40,000 new HIV infections occur in the U.S. each year. The latest estimate, however (derived using antibody tests that can separate recent infections from established ones), is expected to put the annual incidence closer to 60,000 cases per year. Although epidemiologists may haggle over both this estimate and the new global numbers, what’s important to remember is that the various forces and trends driving the epidemic haven’t changed — we’ve just become better at monitoring their impact; hence, the revised numbers.