Call to Primary Care:
Mobilizing to Contain the HIV Epidemic

Editor’s Note:
This question could be interpreted two ways: 1) as a question about NNRTI- or PI-sparing regimens, or 2) as a question about the use of integrase inhibitors and NRTIs. Dr. Wohl and Dr. Hardy have answered each possible interpretation.

Dr. Wohl’s Response:
It is interesting that as we just start to embrace moving to NRTI-free regimens, we forget there was a time when all NRTI-regimens were the rage. Some of us even dabbled in the ‘quad-nuke’ concept to avoid NNRTIs and PIs. Initial study results suggested that zidovudine + lamivudine + abacavir + tenofovir was as effective as an efavirenz-containing regimen. However, a larger trial found that this quadruple NRTI combination led to lower rates of viral suppression compared to tenofovir + emtricitabine + efavirenz and produced double the rate of serious adverse events [Cooper DA et al. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa]. Further, the cumulative use of NRTIs raises the issue of overlapping mitochondrial toxicity. Therefore, for most patients, a quad-nuke regimen is not a good choice, and with newer, novel agents now available, there are probably better options when an NNRTI and PI are to be avoided.

Dr. Hardy’s Response:
Note: I believe that this question is referring to using integrase inhibitors (“IIs”) with emtricitabine/tenofovir for first-line therapy.

With the results of two published randomized, controlled clinical trials (MRK 004 and STARTMRK) comparing the first FDA-approved integrase inhibitor, raltegravir, to efavirenz (each combined with emtricitabine/tenofovir) for first-line therapy, I believe that there is enough evidenced-based data to confidently say the raltegravir can be used with comparable efficacy and safety to that of an efavirenz-based regimen. [See Markowitz M et al. J Acquir Immune Defic Syndr. 2009;52:350-356 and Lennox JL et al. Lancet. 2009;374:796-806. Epub 2009 Aug 3.]

While raltegravir suppressed HIV infection similarly to efavirenz in these two phase 2 and 3 studies and was associated with fewer overall and, specifically, neuropsychiatric side effects, my concerns with its use as a first-line agent center on four areas. 1) It has not been compared to a boosted protease inhibitor-based regimen to date, so we have no data on how it compares to this option for first-line therapy (although by extrapolation from other recent clinical trials, we can probably assume that it will be at least as effective as a boosted PI). 2) As with any newly approved class of medications, longer term safety and efficacy data are always beneficial to know before deciding to abandon older “tried and true” standards for first-line therapy such as NNRTIs and boosted PIs. 3) Although its immediate antiviral potency against HIV replication appears from the studies above to be superior to efavirenz (which previously was known to drop viral load most quickly of all ARVs), the results of the STARTMRK study as well as the SWITCHMRK study have defined the short-term genetic barrier to resistance of raltegravir to be similar to that of a first generation NNRTI (like efavirenz), which is one of the lowest of all ARVs [Eron JJ et al. Lancet. 2010;375:396-407. Epub 2010 Jan 12]. This possibility of rapid selection for integrase inhibitor-resistant strains of HIV may or may not prove to be a factor for choosing a boosted protease inhibitor regimen. 4) Currently, raltegravir is approved for twice-daily dosing, while many other first-line regimens can be given once daily. How much of a hindrance to good adherence this might be is hard to predict, but several patient questionnaires have demonstrated a clear preference for once-daily regimens. Of note, there is an ongoing twice-daily vs once-daily raltegravir clinical trial which is scheduled to produce results in early 2011.

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Dr. Wohl’s Response:
Make it routine. “Everyone is doing it,” we tell patients. Screening for HIV and other STDs is easier than ever, and most people should want to know for sure that they are negative. For HIV testing, you have the weight of the CDC behind you; that should get your patients’ attention. STD screening should be tailored to the risks of your patients in line with current screening recommendations. These have been generally effective, given concerns that undiagnosed STDs can lead to infertility in the case of chlamydia and cervical cancer with HPV. Men who have sex with men need HBV, HCV, and syphilis screening unless they are in a monogamous relationship and already have negative test results.

Dr. Hardy’s Response:
In my experience, the most important factor involved in patient acceptance of HIV screening is the manner in which it is presented to a patient. In general, patients come to see physicians in order to benefit from our medical knowledge and experience. They frequently rely upon us for current, well-grounded medical information and recommendations for their care. In other words, they trust their health to us.

Approaching a patient in a confident, straightforward, nonjudgmental manner in recommending HIV screening goes a long way in having the patient accept the test. Starting a discussion with a statement such as, “I recommend that all my patients be tested for HIV infection at least once and more than once if needed” is a good way to increase a patient’s comfort with the test and deflect any potential feelings of being judged and singled out for testing. Comparing STD screening to other commonly done screening tests such as assessment of blood pressure, weight, blood glucose, and cholesterol testing—for which effective tests also exist—goes a long way in patient acceptance as well.

In ER settings, the offering of “opt-out” testing has demonstrated a >90% acceptance of more than 5,000 patients offered HIV screening [Freeman AE et al. Acad Emerg Med. 2009;16:1156-1164]. Of note, only 2% were considered to be “high risk” by the testers.

For more information on this issue, see:
1. Mahoney MR et al. Am Fam Physician. 2009;80:1441-1444.
2. McCoy SI et al. AIDS Care. 2009;21:1313-1320.
3. Myers JJ et al. J Gen Intern Med. 2009;24:1269-1274. Epub 2009 Aug 5.

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Dr. Wohl’s Response:
This sounds like a false positive. The ELISA is a sensitive test, but it is not specific—just what you want in a screening test. That the confirmatory Western blot was negative strongly suggests a false positive ELISA, as even those in the throes of acute HIV should develop some bands on their Western blot. That you had follow-up testing done that were all negative, clinches our suspicions. This is why it is always prudent to be cautious when reporting an isolated positive ELISA. Patients should be informed that false positives occur and that nothing is conclusive until the confirmatory testing is done. If there is a chance that infection was recent, viral load testing is in order.

Dr. Hardy’s Response:
This situation has become increasingly rare due to the increased specificity of both laboratory-based EIA (or ELISA) and on-site rapid HIV testing. However, when the initial screening test is positive and the confirmatory serologic test (most commonly a Western blot or immunoblot, which is a test with lower sensitivity for detecting antibodies, but greater specificity for identifying antibodies when they are present) is negative, it creates both a diagnostic dilemma as well as a psychosocial one for the ordering physician.

In general, I recommend and teach my trainees to NEVER make a diagnosis of HIV infection (even in a patient with identifiable risk activities) based on a screening test alone. Remember that these tests are to be used for screening purposes only. They must be confirmed by a more specific test. The more specific test can be a Western blot (less expensive) or an HIV RNA by PCR or bDNA technique (more expensive). While the Western blot detects antibodies to HIV, the PCR and bDNA test detect the virus itself and thus will be positive earlier if a patient is in the process of seroconversion.

The explanation of the cause of what appears to be a false positive EIA result is not clear based on the information above. He may be in the midst of seroconversion, which can take a few to several weeks, or a cross reaction with a different, non-HIV antibody in the patient’s blood.

For more information on this issue, see:
1. Mehta SD et al. J Acquir Immune Defic Syndr. 2006;42:116-122.
2. Taval S, Chawla G. Int J STD AIDS. 2009;20:735-736.
3. Barthel HR, Wallace DJ. Semin Arthritis Rheum. 1993;23:1-7.
4. Shima-Sano T et al. PLoS One. 2010;5:e9382.
5. Patel P et al. Arch Intern Med. 2010;170:66-74.

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Dr. Wohl’s Response:
In our complex and multifaceted healthcare system, there is no one answer to this question. Private insurers may cover HIV testing, and Medicare recently approved coverage of the test. As Medicaid becomes more accessible under the recently enacted healthcare reform, more free testing should be available under that plan. Of course, there are other tests that we may order and that our patients have to pay for; for such patients, a frank discussion of the costs is warranted.

The 60-second point-of-care HIV test is available in many countries, including those in Europe and Canada. The company that manufactures the test has applied for FDA approval after conducting studies of the performance of the test and more news regarding the test’s application is expected this year.

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Dr. Wohl’s Response:
Cost effectiveness of a medical test is a tricky concept. To some, it can mean an actual savings of money while in reality it has to do with the value of money spent to provide the intended benefit. So, if widespread testing in a developing country costs millions of dollars and detects HIV in 15% of those tested, who then are counselled regarding safer sex, are evaluated for the need for antibiotics to prevent opportunistic infections, and are ultimately treated for HIV, this may not save anyone money (although when the benefits of averted transmissions, work days not lost, and prevention of orphaned children are added up, it may), but it was a good value for the dollars spent. For many developing nations, it is not the cost of the HIV testing that is prohibitive; it is the cost of not testing that will cost so much more in the long run.

Dr. Hardy’s Response:
There are several options for HIV screening that have been evaluated in developing countries, where the burden of HIV infection is much higher than it is in the United States.

In general, because of the much greater prevalence of HIV infection among the general public in countries in sub-Saharan Africa (ranging from 1% to 35%) and the enormous economic and human costs of the morbidity and mortality of AIDS, cost-effectiveness of identify and treating HIV is even more clear than in the US. One major difference is the amount of resources available to conduct testing and offer treatment. This, of course, remains a major issue. In the meantime, oral, finger stick, and dried blood spot methods have been tested in Africa and India. One concern there, although not really a concern in the US, is the possibility of false positive tests due to concurrent infections such as tuberculosis [Swaminathan S et al. AIDS Res Hum Retroviruses. 2008;24:941-946].

Comparative evaluation of some of the tests currently used in developing countries can be found in the references below.
1. Lilian RR et al. J Clin Virol. 2010 Mar 6. [Epub ahead of print].
2. Lyamuya EF et al. BMC Infect Dis. 2009;9:19.
3. Dessie A et al. Ethiop Med J. 2008;46:1-5.
4. Syed Iqbal H et al. J Clin Lab Anal. 2008;22:178-185.
5. Iqbal HS et al. Clin Diagn Lab Immunol. 2005;12:1425-1428.
6. Doyle NM et al. Am J Obstet Gynecol. 2005;193(3 Pt 2):1280-1285.
7. Pinkerton SD et al. AIDS Care. 2009;21:1157-1162.

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Dr. Wohl’s Response:
Varicella zoster is not uncommon among HIV-infected individuals. When seen, it should trigger consideration of HIV testing in patients of unknown HIV status. For those with diagnosed HIV infection who develop shingles, early treatment with acyclovir or similar drugs can be beneficial in reducing the duration of lesions and may also lessen the risk of post-herpetic neuralgia. When zoster develops early in the course of HIV therapy, it may be a consequence of antiretrovirals being administered a bit too late to improve immune function and forestall the reactivation of latent VZV. Alternatively, zoster soon after HIV therapy initiation may be an immune reconstitution phenomenon. A study in Spain of 316 patients starting antiretroviral therapy found that 8% developed zoster within 4 months, and the risk appeared to be linked most closely to the rise in CD8+ cells during therapy [Domingo P. Am J Med. 2001;110:605-609]. As with most immune reconstitution syndromes, interrupting HIV therapy is only done as a last resort. For all but the most severe cases of zoster soon after ART, treatment with anti-VZV therapy is all that will be required, and HIV therapy can be continued.

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