HIV-infected patients

The Challenge of Curing HIV

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In two HIV-infected patients who had no detectable virus after hematopoietic stem-cell transplantation, HIV rebounded following discontinuation of antiretroviral therapy.

 The success of combination antiretroviral therapy (ART) in suppressing HIV replication led to cautious optimism in the mid-1990s that HIV could be cured. The recognition in 1997 that HIV persists in long-lived reservoirs, however, dashed those hopes. Therefore, the report in 2009 that an HIV-infected man (“the Berlin patient”) was cured of infection after allogeneic hematopoietic stem-cell transplantation (HSCT) for leukemia came as a surprise. After that success, investigators in Boston reported that two HIV-infected men had no detectable HIV following HSCT. (Unlike the Berlin patient, whose donor lacked an HIV co-receptor, the Boston patients received HSCTs from HIV-susceptible donors.) To test the hypothesis that they too may be cured of infection, both Boston patients underwent carefully monitored ART interruption. The results, first reported last year, have now been published.

Before treatment interruption, both patients underwent exhaustive HIV testing: No virus could be detected in peripheral blood, even on sensitive assays using ≥150 million CD4 cells. One patient underwent rectal biopsies, and no HIV DNA was detected. Immune responses against HIV declined in both patients, suggesting that little-to-no virus antigen was present. Genetic testing showed that <0.001% of peripheral blood cells were of host origin.

Following these careful studies, both patients stopped ART under close supervision. In patient A, HIV RNA was first detected in blood about 12 weeks after discontinuing ART, and it rapidly increased to >4 million copies/mL; he developed symptoms of acute retroviral syndrome (ARS) and evidence of HIV-associated meningitis. Patient B went almost 8 months before viremia rebounded to 1.9 million copies/mL; he, too, developed symptoms consistent with ARS. After resuming ART, both patients eventually achieved HIV RNA levels <50 copies/mL.

COMMENT

These cases highlight that techniques for detecting HIV are not yet sensitive enough to confidently predict whether a patient is free of infection; clearly, a high priority is to develop better assays of virus persistence. Another implication is that despite substantial reductions in HIV DNA levels in blood following HSCT — estimated to be >1000-fold in these patients — persistence of virus in even a few cells can rekindle viremia when ART is stopped; indeed, recent modeling suggests >10,000-fold reductions may be needed to prevent HIV rebound. Clearly, this report and that of virus rebound in the Mississippi child emphasize the challenges in eradicating HIV. Although sobering, the results should inspire us to redouble efforts to develop new strategies, such as prodding HIV out of hiding so that it is vulnerable to novel agents or immune-mediated elimination. As an editorialist concludes, “we still have much work to do.”

– See more at: http://www.jwatch.org/na35230/2014/08/01/challenge-curing-hiv#sthash.R9zzkiWb.dpuf

Cholesterol Guidelines May Underestimate Cardiovascular Risk in HIV-Infected Patients – See more at: http://www.jwatch.org/na35651/2014/09/09/cholesterol-guidelines-may-underestimate-cardiovascular#sthash.fanWUptz.dpuf

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Although new guidelines recommend statin use in more HIV-infected patients, most of those with evidence of coronary plaque are still not flagged as needing therapy.

 Cholesterol guidelines released in 2013 recommend statin therapy for, among others, patients aged 40 to 75 with a 10-year atherosclerotic cardiovascular disease (CVD) risk ≥7.5%, as estimated by a new calculator. Whether this recent guideline, which was designed for the general population, is better than the 2004 Adult Treatment Panel III guidelines at predicting CVD — or at appropriately recommending statin use — in HIV-infected patients is not known. Now, investigators have examined the performance of the new and old guidelines in a cohort of HIV-infected patients.

A total of 108 patients without known CVD underwent coronary computed-tomography angiography (CCTA). The median age was 46 years, 50% were current smokers, and 20% were receiving antihypertensive medications. Despite the relatively low overall 10-year atherosclerotic CVD risk score (3.3%), 36% of participants had high-risk–morphology plaque detected on angiography. When the new and old guidelines were applied, several striking findings emerged:

  • In the overall study population, statins would be recommended for 21% by the 2013 guidelines versus 8% by the 2004 guidelines.

  • Among patients with high-risk–morphology coronary plaque, statins would be recommended for 26% by the 2013 guidelines and 10% by the 2004 guidelines.

  • Among patients without coronary plaque, statins would be recommended for 15% by the 2013 guidelines versus 5% by the 2004 guidelines.

COMMENT

The main limitation of this study is that detection of high-risk–morphology plaque on CCTA is not yet known to be predictive of CVD risk — or statin benefit — in HIV-infected patients. Nevertheless, the finding that 74% of HIV-infected patients with high-risk–morphology plaque would not qualify for statins even by the more-encompassing 2013 guidelines is alarming. Would HIV-infected patients who do not meet current guidelines benefit from statin use? A randomized clinical trial to address this question is in the offing.

– See more at: http://www.jwatch.org/na35651/2014/09/09/cholesterol-guidelines-may-underestimate-cardiovascular#sthash.fanWUptz.dpuf

Single-Pill Regimens for HIV-1 Infection.

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In the latest Clinical Therapeutics review, a 52-year-old man with a history of HIV-1 infection and poor medication adherence presents for evaluation. A single-pill regimen is considered. For some patients with HIV-1 infection, combination regimens consisting of one pill to be taken daily can improve adherence.

With the advent and refinement of combination ART [antiretroviral therapy], the life expectancy of HIV-infected patients has risen dramatically. In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners. If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.

Clinical Pearls

• What are the currently available single-pill combinations marketed for HIV-1 treatment?

There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF-FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF-FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF-FTC combined with 150 mg of the integrase strand-transfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth single-pill combination has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir DTG).

• In which patient populations should single-pill combinations be generally avoided?

Single-pill combinations should be avoided in patients with clinically significant renal disease because TDF, TC, and FTC all require dose reductions or elimination when the estimated creatine clearance is less than 50 ml per minute. The inability to adjust the dose of individual drug components in patients with renal insufficiency is an important limitation of single-pill combinations. In addition, patients who have drug-resistant HIV-1 infection often require agents that are not included in single-pill combinations.

Morning Report Questions

Q: When should a regimen containing a protease inhibitor be used?

A: None of the current single-pill combinations contain protease inhibitors, which should be used in patients with known viral resistance to NNRTIs or INSTIs. In addition, because transmitted resistance to protease inhibitors is uncommon and resistance to this class emerges relatively slowly, protease inhibitors are often favored when treatment decisions are required before resistance-testing results are available — for example, in the case of patients with acute HIV-1 infection or opportunistic infections. Protease inhibitors are also sometimes considered in patients with inconsistent adherence because multiple viral mutations are required to compromise the activity of these agents.

Q: How do currently available anchor medications for once daily regimens compare?

A: EFV, the anchor drug in EFV-TDF-FTC, is potent and, in recent years, the drug to which every newly developed anchor antiretroviral agent has been compared. EFV may cause neuropsychiatric effects (e.g., vivid dreams, insomnia, somnolence, and depression) or rash, although symptoms typically diminish over time. EFV is the preferred NNRTI during pregnancy, when initiated 8 weeks after conception. Rilpivirine (RPV)-based regimens are not recommended for patients whose pretherapy HIV-1 RNA level is more than 100,000 copies per milliliter or whose CD4+ T-cell count is 200 per cubic millimeter or less. RPV must be taken with a solid meal (greater than or equal to 390 kcal) and requires stomach acid for adequate absorption, precluding the concomitant use of proton-pump inhibitors. In addition to its use in initial therapy, RPV-TDF-FTC may have a role in patients with virologic suppression during treatment with a protease inhibitor-containing regimen who have a reason to change medications: in a recent trial, switching such patients to RPV-TDF-FTC maintained high rates of virologic suppression and improved lipid levels. Cobicistat-boosted EVG does not have neuropsychiatric effects and does not commonly cause rash. However, cobicistat inhibits tubular secretion of creatinine without reducing the creatine clearance. As a result, patients may have a mild increase in the serum creatinine level, typically less than 0.4 mg per deciliter (35 micromoles per liter), with this medication initially.