HIV and Methicillin-resistant Staphylococcus Aureus (MRSA)

HIV-infected patients could increase the risk for Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection, including bloodstream infection. A study reported that the incidence of methicillin resistant Staphylococcus aureus (MRSA) bacteraemia increased significantly in HIV-infected patients from 2000 to 2004. Injection drug use (IDU), end-stage renal disease (ESRD) and CD4 count <200 cells/μL were independent predictors for incident MRSA bacteraemia, while ESRD was more common in patients with MRSA bacteraemia than methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. IDU, ESRD and CD4 count <200 cells/μL factors may serve as important clinical markers of MRSA likelihood in decisions regarding initial antimicrobial management.

Initial antimicrobial therapy for presumed sepsis in HIV-infected patients may require agents active against MRSA, including vancomycin, linezolid and, in nonpulmonary infections, daptomycin, particularly in patients with risk factors for MRSA bacteraemia.

(HIV Med. 2008;9(10):858-862)

CD4 Cell Count and AIDS-Defining Malignancies (ADM)

CD4 cell count is strongly associated with the risk of death from both AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM). Non-AIDS events have become an important cause of mortality as individuals with HIV infection survive to older ages and have started to suffer from similar age-related diseases to the HIV-uninfected population.
Rate of death of nADM is higher than from ADM in all patients other than those with very low CD4 cell counts. Lung cancer is the most common fatal nADM, concordance with the high prevalence of smoking among the HIV-infected population.
Age is also a strong predictor of death from malignancies, suggesting that, at similar CD4 cell counts, older patients are at greater risk of dying from malignancy. This may be a consequence of the higher incidence of cancers in older individuals, as well as an increased likelihood of death in older individuals, irrespective of the cause. However, this may also reflect reduced immune system activity in the elderly. Interestingly, the HIV RNA level was only weakly associated with ADM mortality and was not independently associated with nADM mortality.
Non-AIDS-defining malignancies was related to combination antiretroviral (cART) exposure. The individuals taking effective cART are less likely to die from ADM and, as a result, may be more likely to die from nADM. In contrast, patients dying from ADM may be more likely to have stopped or never received cART.
(AIDS. 2008;22(16):2143-2153)

Maraviroc, The CCR5 antagonists

Maraviroc (Celsentri or Selzentry; Pfizer Ltd., Sandwich, UK) belongs to a new class of anti-HIV drugs named CCR5 antagonists, which block HIV entry into cells. Viral entry is an attractive step for the development of new agents against HIV variants resistant to current antiretroviral drugs. HIV gains entry into CD4-expressing cells through a series of sequential interactions between the envelope glycoprotein gp120 and the CD4 receptor and one of two coreceptor molecules, chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4), which are expressed on the surface of target cells. Maraviroc specifically inhibits the replication of R5-tropic HIV variants by an allosteric mechanism after binding to the transmembrane CCR5 coreceptor cavity. Because of its exclusive activity against CCR5 tropic strains, viral tropism testing is mandatory before using CCR5 antagonists in the clinic.

Maraviroc is a substrate for the P-glycoprotein and the cytochrome P450 (3A4), both of which are involved in the metabolism of multiple other agents, including several antiretroviral drugs. Therefore, drug interactions using maraviroc should be kept in mind. Briefly, the standard 300 mg twice daily dose of maraviroc does not require changes when the drug is given concomitantly with methadone, statins, nevirapine, cotrimoxazole, etinilestradiol nor pegylated interferon and ribavirin. However, dose adjustments have to be made when maraviroc is used along with some potent inhibitors or inducers of CYP3A4.
(AIDS. 2008;22(17):2231-2240).

New Guidelines for HIV Treatment

In AIDS 2008-XVII International AIDS Conference, the International AIDS Society–USA recommends new guidelines for HIV treatment. This recommendation is simplified and strengthened. One change in the recommendations is a greater emphasis on full virologic suppression. In this recommendation, deciding whether to start treatment in patients with a CD4 cell count of 350 cells/μL or more should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient willingness to begin treatment. Individuals with incomplete virologic suppression have greater morbidity and mortality than those who more completely suppress it.
The guidelines move aggressively toward earlier initiation of antiretroviral therapy. Treatment should be started before CD4 cell count decreases to less than 350/μL if there are correlates of faster HIV disease progression such as high plasma viral load (>100,000 copies/mL), rapidly decreasing CD4 cell count (>100/μL per year), active hepatitis B or C virus coinfection (resulting in faster progression of liver disease), cardiovascular disease risk, and HIV-associated nephropathy. Initiation of therapy in patients within the 200 to 350/μL CD4 cell count range should be strongly considered and individualized. The recommendations to start therapy in any patient with symptomatic HIV disease, regardless of CD4 count or viral load, and asymptomatic patients with less than 200/μL CD4 cell count.
Clinicians are encouraged to evaluate the whole patient, not just the status of HIV disease, but all coexisting conditions. Resistance testing should be conducted in all patients as part of their baseline workup. There is a little change in recommendations for an initial regimen in patients who are not infected with resistant virus. The first-line choice is a backbone of either an NNRTI or a ritonavir-boosted protease inhibitor (PI), combined with a dual nucleoside reverse transcriptase inhibitor (NRTI) component. The initial treatment regimen for HIV infection must be individualized, particularly in patients with comorbid conditions, but typically includes efavirenz or a ritonavir-boosted PI plus 2 NRTIs (tenofovir or emtricitabine or abacavir or lamivudine). Better not using darunavir as part of an initial regimen but holding it in reserve to use with patients who develop resistance to other PIs. Current first-line regimens are good and simple to use, and there is still concern about holding some drugs in reserve for patients who develop resistance to existing drugs. Even in heavily pretreated patients, the goal of treatment is an HIV-1 RNA level below assay detection limits. Treatment failure should be promptly identified and managed.

Depending on the NRTI mutations present, one might want to consider use of etravirine. Failure of a PI-based regimen can be more complicated, depending upon the genetic barriers. If caught early, changing the NRTI component to 2 active drugs might be sufficient to save the regimen. But as resistance points accumulate, one should consider use of darunavir or tipranavir.

The 3 drugs approved since the last version of the guidelines in 2006 are maraviroc, the first drug to target the CCR5 co-receptor on the surface of the cell; raltegravir, the first drug in the integrase inhibitor class; and etravirine, a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with clear activity against some NNRTI-resistant viruses. Enfurvitide remains an important option for the heavily treatment experienced population, but problems associated with daily injections and the emergence of other therapeutic alternatives such as raltegravir or maraviroc have reduced its use.

(AIDS 2008: XVII International AIDS Conference. Antiretroviral Treatment of Adult HIV Infection, 2008 Recommendations of the International AIDS Society–USA Panel. Presented August 3, 2008. JAMA. 2008;300:555-570)