HIV UPDATE David C. Bright, O.D., FAAO Professor, Southern California College of Optometry / M B Ketchum University VHA West Los Angeles Health Center INTRODUCTION Updates on HIV are always a mix of good news and bad news Good news: more drugs introduced, with generally good tolerance, and potency. Tolerance has improved quite a bit: the frequencies of anemia (zidovudine/retrovir ), GI upset (earliest protease inhibitors), and neuropathy (stavudine/zerit ) are significantly reduced, since these older drugs are no longer top choices for therapy. Good news: greater ease of testing, with potential identification of newly infected individuals (this is a huge advance over previous methodologies). Good news: potential for individuals treated soon after infection to achieve a functional cure Bad news: only ¼ of HIV-infected individuals in the US achieve full viral suppression Bad news: despite increased access to testing, the number of estimated new infections per year has not declined but remains steady at about 50K per year in the US. INTEGRASE INHIBITORS (INSTI) 2 new drugs in 2012-2013 Initial drug = raltegravir (ISENTRESS ), FDA approval October 2007. Advantages with this drug: better tolerated than efavirenz (less CNS toxicity, less interference with lipids). There is a not optimal barrier to resistance, however. Two newer drugs introduced: elvitegravir (only available in a 4-drug coformulated single tablet, FDA approved August 2012, STRIBILD ), and dolutegravir (TIVICAY ), approved August 2013. Both of these are once-daily. Elvitegravir + cobicistat [booster drug analogous to low-dose ritonavir] + emtricitabine [FTC] + tenofovir = STRIBILD. Advantage is the once-daily dosing. Disadvantages are fairly significant cross resistance with raltegravir (neither drug has a high barrier to resistance), and the trickiness of the booster, cobicistat which can raise lipids and also has some complicated drug-drug interactions similar to ritonavir, the protease inhibitor boosting drug. Dolutegravir (TIVICAY ) has the highest barrier to resistance of the 3 integrase inhibitors (the acronym is INSTI or integrase strand transfer inhibitor ), and it is strongly recommended in both the 2014 versions of the NIH/HHS treatment guidelines and the IAS (International Antiviral Society).
Few pills ISENTRESS combo (raltegravir twice daily, Truvada/tenofovir-emtricitabine once daily); STRIBILD (one pill); TIVICAY (dolutegravir once daily, with Epzicom /abacavirlamivudine once daily or Truvada /tenofovir-emtricitabine once daily) Compared to protease-inhibitor based regimens less problems with drug-drug interactions and CYP450, less interference with lipids for the raltegravir or dolutegravir-based regimens. PROTEASE INHIBITORS (PI)- no new drugs but a shift away from older to newer drugs The oldest drugs have fallen by the wayside: Saquinavir hard-gel (Invirase ) still available but soft-gel variety (Fortovase ) was off the market in 2006. Indinavir (Crixivan ) available but little used, given its toxicities however, this was the star of the first 3 protease inhibitors released in 1995-1996. Nelfinavir (Viracept ) available but little used, not recommended by HHS (inferior virologic efficacy). Amprenavir (Agenerase ) was off the market in 2006. Ritonavir (Norvir ) is only in use as a booster, in small doses. Tipranavir (Aptivus ) not widely in use, not an HHS recommended choice (inferior antiviral activity, more toxicity, and more drug-drug interactions). What drugs remain as alternative choices? Lopinavir + ritonavir (Kaletra ) was a mainstay 5+ years ago. Fosamprenavir (Lexiva ), best if boosted with RTV alternative choice per HHS. Atazanavir (Reyataz ), best if boosted with RTV still a first choice per HHS and IAS Darunavir (Prezista ), must be boosted with RTV still a first choice per HHS and IAS Advantages of PI-based ART: high barrier to development of viral resistance, and fortunately very slow development of resistance to the NRTI (nucleoside reverse transcriptase inhibitor) backbone drugs; protease inhibitor regimens are forgiving in patients who have suboptimal adherence to the drug regimen. HHS approved drugs (boosted darunavir and boosted atazanavir) are once-daily. Disadvantages of PI-based ART: drug-drug interactions via CYP450 system, mainly related to ritonavir (interacts with many non-hiv drugs); interference with lipids, can drive up cholesterol levels, can increase risk of cardiovascular disease and additionally increase the risk of diabetes NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) 1 new drug in 2011 Nevirapine (Viramune ) still used in prevention of mother-to-child transmission (MTCT) of HIV; not a first choice HHS regimen, nor a second (alternate) choice of HHS; problems in people with hepatic impairment. This drug is now available as a generic. Delavirdine (Rescriptor ) not in use at all, due to poor antiviral performance Efavirenz (Sustiva, or coformulated with TDF/FTC as Atripla ) potent drug, best performer of the initial three NNRTIs; still a first-choice HHS regimen per simplicity of Atripla, single pill once daily. Toxicities include CNS toxicity, dyslipidemia, skin rash. Efavirenz will go generic this year. Etravirine (Intelence ) FDA approved 2008; not an HHS first choice; for multidrug resistant strains of HIV.
Rilpivirine May 2011 FDA approved as single drug (Edurant ); August 2011 FDA approved as coformulation (Complera ), with FTC and TDF; is an alternative first-choice HHS regimen, with some caveats. ANTIRETROVIRAL THERAPY (ART) RECOMMENDED FOR ALL PATIENTS The HHS guidelines urge consideration of ART for any HIV-infected patient; the forcefulness of the recommendation depends on the patient s CD4 pre-treatment, and the strength of the recommendation increases as the pre-treatment CD4 count goes lower. < 350 has an AI recommendation (strongest recommendation, based on RCT) 350-500 has an A II recommendation (strong, based on nonrandomized or observational) > 500 has a B III recommendation (moderate, based on expert clinical opinion). The rationale for treatment for any and all, based on expert opinion, looks at (1) reduced likelihood of transmission of HIV to others the smaller the inoculum, the less the likelihood of transmission of HIV & infection; (2) less likelihood of developing resistance to ARV drug classes when starting with higher CD4 counts. Benefits accrue: lower risk of infecting others (steady or sporadic sexual partners), greater likelihood of achieving higher or normal CD4 counts with earlier rather than later initiation of therapy, reduced risk of both HIV-related and non-hiv related diseases with earlier initiation of therapy, reduced level of HIV in the community (a population-level decrease ) with reduced morbidity, mortality, and HIV transmission. Mantra is treatment is prevention. The other slogan used is test and treat. However, testand-treat ultimately has its largest benefits when the patient continues through the cascade following testing, to engagement with the diagnosis, understanding and committing to the value of therapy for themselves and for others around them, enrollment in and retention in the healthcare system, and full adherence to the drug regimen. Additionally, test and treat works best when there are very high rates of HIV testing and treatment to catch early infected individuals (something that will be quite challenging in terms of both cost and personnel). RECOMMENDED REGIMENS FOR COMBINATION ANTIRETROVIRAL THERAPY (cart) from HHS (Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May 2014) and from International Antiviral Society-USA Panel (Günthard HF et al; JAMA 2014; 312(4):410-425) INSTI-based regimens Dolutegravir plus tenofovir/emtricitabine fixed coformulation (Tivicay plus Truvada ) Dolutegravir plus abacavir/lamivudine fixed coformulation (Tivicay plus Epzicom ) Elvitegravir/cobicistat/tenofovir/emtricitabine fixed coformulation (Stribild ) Raltegravir plus tenofovir/emtricitabine fixed coformulation (Isentress plus Truvada )
NNRTI-based regimens Efavirenz/tenofovir/emtricitabine fixed coformulation (Atripla ) Efavirenz plus abacavir/lamivudine fixed coformulation (Sustiva plus Epzicom ) Rilpivirine/tenofovir/emtricitabine fixed coformulation(complera ) Ritonavir-boosed protease inhibitor regimens Atazanavir plus tenofovir/emtricitabine coformulation (Reyataz plus Truvada ) Atazanavir plus abacavir/lamivudine coformulation (Reyataz plus Epzicom ) Darunavir plus tenofovir/emtricitabine coformulation (Prezista plus Truvada ) The boosting dose of ritonavir is typically 100 mg (original regimens using ritonavir as the sole PI dosed it at 600 mg twice daily) EPIDEMIOLOGY IN THE US CDC estimates about 1.1 million HIV infected in the US; about 16% are unaware of their infection; less than 25% of patients on treatment have achieved full viral suppression. The number of new infections each year seems to remain unchanged, at about 50K per year. African Americans have the highest burden of HIV among ethnic groups in the US: an estimate of 44% of all new infections in individuals 13 years and older in 2010 occurred in African Americans, despite representing only 12% of the US population. The 2010 estimated rate of new infections in African American men was 7-fold higher than for white men, 2-fold higher than for Latino men, and 3-fold higher than for African American women. Infections among US men who have sex with men (MSM), the number of incident new infections remains high and has not declined. The subgroup (African-American MSM) is probably the most concerning, since the incidence is a good deal higher, despite the lower number of cases on the whole. In 2010, more new HIV infections occurred in gay or bisexual African American males (aged 13-24) than in any other subgroup of gay and bisexual men: 72% of new HIV infections among African American men occurred in MSM. Contrasting the above with world wide data, in which there are actually fewer new infections than some years ago this is good news! The decrease in new infections since 2001 is about 33%. NEW TREND: evaluating long-acting drug regimens Rilpivirine (Edurant), a second generation NNRTI GSK744 (GSK 1265744), an analogue of dolutegravir (not yet released) Formulated to be given once or twice monthly
Clinical trials are evaluating carefully how to combine these at the start of therapies with NRTIs scheduling the long-acting drug vs. the short-acting accompanying drugs is tricky. In clinical trials for both prevention of infection in at-risk people (this is long-acting pre-exposure prophylaxis, or PrEP) and for therapy for HIV-infected individuals. NEW TREND: finally new guidelines for post-exposure prophylaxis (PEP) Last version of guidelines dated from 2005, with frustrating instructions to evaluate the level of risk of the contact, which then shifted choice of treatment into either a dual- or triplecombination regimen (flying in the face of the critical need for definitive viral suppression), and using older (and outdated) drugs. Recent update published 2013; leaves out the dual- vs. triple-combination choice Prime recommendation: raltegravir BID plus Truvada QD Alternatives are choice of: boosted darunavir, etravirine, rilpivirine, boosted atazanavir, or Kaletra as the potent component plus Truvada; tenofovir + 3TC; zidovudine + 3TC (or coformulated Combivir); or ZDV + emtricitabine. Who should get this? Only to individuals who have had mucosal contact with infected blood or genital secretions or to health care workers who have needle stick exposures to HIV-infected source patients. NEW: PrEP (Pre-Exposure Prophylaxis) Use of tenofovir/emtricitabine (Truvada ) on a daily basis to prevent infection in the at-risk patient Challenges existing with this strategy are optimizing adherence and insurance coverage, not whether it works. When the pills are taken regularly, it works. Success rates are extremely variable at this time, fully depending on the patient s compliance. The greatest successes occur with highly compliant patients (as high as 99% reduction of infection). The success of this strategy is directly correlated to blood levels of the drug. The high cost is not that easy to justify for all patients but is justifiable when used in the highest at-risk groups. NEW TREND: Cures There is the sterilizing cure only one person, the Berlin patient. There is the functional cure this is the Mississippi baby who had] HIV infection herself, not transmitted at birth, was treated at birth and briefly after birth, then off therapy for longer than 1 year but has virologic control. The most recent (bad) news about the Mississippi baby is that HIV has now been detected. Also there is the subset of French patients in the VISCONTI cohort,
treated early in the course of infection that have remained off ART for months or years, without treatment or detectable virus. Presumably the early treatment limits the heavy infection of the viral reservoir of long-lived memory cells. NEW TREND: Fourth Generation HIV Test and Sequencing Combines the standard HIV antibody but assists at differentiation of HIV-1 vs. HIV-2 The Western Blot, considered a gold standard test, measures the virus itself, not the antibodies to HIV but the WB is able to detect virus only after seroconversion, which is typically 2-3 months after initial viral transmission. The ELISA antibody test is similar, in being able to detect antibodies produced after the immune system can produce them, again 2-3 months after transmission. The p24 antigen detects viral presence before seroconversion. Impact: catch people when they are most readily infectious, and potentially start therapy as early as possible, with the potential to limit to amount of HIV-infected memory cells in reservoirs (and reduce their likelihood of infecting others). Testing sequence note that there are 3 tests done in succession with a variety of outcomes, but the new value is the detection of acute HIV-1 infection o Antigen/antibody combination (fourth generation) immunoassay (test 1) tests for presence of antibodies to both HIV-1 and HIV-2, thus noting established infection, and: o Additionally tests for HIV-1 p24 antigen for acute infection o If the test is negative, no further testing is needed o If the test is positive, then a differentiating antibody immunoassay (test 2) is done to separate HIV-1 from HIV-2 antibodies. Results can be positive for HIV-1 antibodies, positive for HIV-2 antibodies, or undifferentiated between HIV-1 and HIV-2 antibodies o If the initial test (combo)is reactive but the second test (differentiating) is nonreactive or indeterminate, then the HIV-1 NAT test (nucleic acid test) (test 3) is done. o A reactive HIV-NAT result (test 3) with a nonreactive differentiation (test 2) best indicates laboratory evidence for acute HIV-1 infection. o A reactive HIV-NAT result (test 3) and indeterminate differentiation (test 2) indicates presence of HIV-1 antibodies confirmed by HIV-NAT. o A negative HIV-NAT result (test 3) and nonreactive or indeterminate differentiation (test 2) indicates a false-positive on the initial immunoassay (test 1). NEW TREND: P4P4P pay for performance for patient Controversial use of financial or other rewards for increased compliance/adherence
Has been found to improve compliance and patient outcomes with weight loss, hypertension, measurement of INR, and diabetes, all chronic diseases and HIV infection is a chronic disease as well. This approach may be applicable to HIV clinical care as well. It may be a viable way to avoid the very frequent lapses in care in the cascade that would otherwise improve chances of successful treatment, with all the attendant benefits. This approach is being tested in Washington DC, and in the Bronx, NY. NEW TREND: increasing generic drug availability No protease inhibitors are available as generics yet. A single NNRTI (nevirapine) is available. Of the backbone drugs, tenofovir (Viread) and emtricitabine (Emtriva) are still copyright protected, but most of the older NRTIs are generics. Constructing a well-tolerated and effective 3-drug combination out of generics is not easy: the only potent drug (nevirapine) has some challenges (not for men with a starting CD4 of > 400, not for women with a starting CD4 < 250) and the drugs used in combination with it are more toxic and less well-tolerated. Lamivudine (3TC) is expected to go generic in 2014. This is good news, in that 3TC is a commonly used add-on to the backbone. Efavirenz is expected to go generic in 2014. This is a potent, successful, and very useful drug burdened with some tolerability issues and systemic toxicities. It will be possible to build a nearly generic regimen around it that mimics Atripla: generic efavirenz, generic lamuvidine (quite similar to FTC/emtricitabine) but still needing branded tenofovir (Viread). The challenge will be 3 separate pills, not a single pill. The other challenge will be insurance coverage, favoring the generic mash-up instead of the easier to use branded coformulation. What drugs have gone or will be going generic: o 2012: zidovudine/retrovir, lamivudine/epivir, stavudine/zerit, didanosine/videx, saquinavir hard gel/invirase, nevirapine/viramune o 2013: ritonavir/norvir, efavirenz/sustiva, zidovudine-lamivudine/combivir o 2016: abacavir/ziagen, lopinavir-ritonavir/kaletra o 2017: atazanavir/reyataz, tenofovir/viread, darunavir/prezista o 2019: etravirine/intelence o 2024: tenofovir-emtricitabine/truvada WHAT ABOUT THE EYES Ocular opportunistic infections still behave the same way: likeliest with marked immunocompromise, so the likelier patients will be those undiagnosed and seriously immunodeficient, or patients who are failing on therapy (for a variety of reasons). The sheer number of cases of CMV retinitis has definitely declined, thanks to increased levels of immune restoration (recall that CMV-R is most common with CD4 of 50 or less). Pre-cART
incidences for CMV retinitis were 20 or more new cases per person-year; post-cart incidence has dropped to about 5.6 new cases per 100 person-years. Patients demonstrating consistent immune reconstitution from successful cart (increase of CD4 count of 100 cells on 2 consecutive visits 6 months apart) have been able to discontinue on-going CMV retinopathy therapy. Research into eye issues with AIDS has extended beyond CMV retinitis into areas of retinal and visual function. Much study has been done on hemorheological abnormalities (blood cell size, shape, rigidity, and flow), retinal dysfunction (sometimes known as neuroretinal disorder ), and on contrast sensitivity. o Blood flow was reduced, due to increased erythrocyte aggregation and increased leukocyte rigidity. Abnormalities also included reduced deformability (thus impairing passage of erythrocytes through small vessels), and higher but not abnormal levels of fibrinogen (higher than seen in normal controls). o Contrast sensitivity studied in the LSOCA (Longitudinal Studies of the Ocular Complications of AIDS cohort). Reduced contrast sensitivity felt to be related to retinal damage and loss of ganglion cells. The proposed sequence is retinal microvasculopathy, leading to neuroretinal disease, leading to abnormal contrast sensitivity. Detectable reductions in contrast sensitivity were linked to higher risk of mortality globally. Reduced contrast sensitivity was related (not consistently) to lower CD4 cell counts. Later studies (with equipment able to detect this) noted a correlation between thinning of the RNFL and defects in both contrast sensitivity and color vision. o Retinal vasculature was also evaluated: changes in both arterial and venular caliber were associated with a higher risk of mortality, suggesting widespread vascular changes, including cerebral and coronary vasculature. On a microscopic level, there was detection of narrowing of the retinal capillary lumina, loss of pericytes, and thickening of the basal lamina. However, microvascular changes (which are universal) are probably insufficient to cause the frequently observed cotton wool spots ( HIV retiopathy ). Perhaps an equally important role for eye care providers is to act as members of the healthcare team, spending time communicating with the patient about global issues, providing encouragement and prodding for the patient s good. We ask and nag about blood glucose and a1c results, so is this really any different? CONCLUSIONS
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