Blistering Hands


Case Study: A 48-year-old male presents with blisters and sores on his dorsal hands. The patient is a former intravenous drug abuser and carries a diagnosis of hepatitis C virus infection, which has been untreated to date. He reports moderate alcohol consumption, but otherwise states he uses no illicit substances and takes no medications. He notes the lesions are generally asymptomatic, though the erosions are tender.

  • Review of systems is otherwise unremarkable; the patient is currently afebrile, and denies night sweats, cough, chills, unintentional weight loss, or gastrointestinal complaints.
  • Physical exam reveals diffuse hyperpigmentation and hirsutism. There are no lesions in skin overlying the genitalia, axillae, nipples, or trunk.

LEARNINGS

This patient has classic features of porphyria cutanea tarda (PCT), with flaccid, easily ruptured bullae with resulting erosions, signs of skin fragility, and some scarring. He also has diffuse hyperpigmentation and increased hair growth, both commonly seen in PCT. PCT is due to abnormal uroporphyrinogen decarboxylase, which can be inherited or acquired; most cases are acquired. Causes of PCT include hemochromatosis, alcohol, hepatitis, or other sources of liver injury. The diagnosis can be confirmed by visualizing fluorescence of urine under Wood’s lamp examination, or through formally measuring the urinary porphyrin levels. Uroporphyrinogen decarboxylase activity can be measured as well. Patients should be evaluated for diseases which can affect the liver, including, potentially, hemochromatosis (HFE gene testing is widely available). Treatments include sun avoidance (as patients are often photosensitive), treatment of underlying liver disease, and prevention of further liver damage (i.e. alcohol avoidance). Smoking may worsen the disease, and patients should receive tobacco cessation counseling and assistance. Iron stores may be reduced by therapeutic phlebotomy. Some patients benefit from antimalarial therapy, particularly if they cannot undergo or tolerate phlebotomy.

Management & Therapy Tips

  • Porphyria cutanea tarda can present with photosensitivity, hyperpigmentation, hypertrichosis, and skin fragility manifesting as flaccid, fragile bullae, shallow erosions, and small scars on the dorsal hands
    • PCT is due to underlying uroporphyrinogen decarboxylase deficiency, often due to underlying liver disease
    • Patients should be screened for causes of liver disease and avoid further hepatotoxic agents
  • Management includes sun protection, avoiding liver toxicity, and smoking cessation
    • Phlebotomy may be used to lower total iron stores
    • Antimalarial drugs may help patients who cannot tolerate phlebotomy or in whom phlebotomy is contraindicated

Preexposure Prophylaxis for HIV: Where Are We Now and How Did We Get Here?


In July 2012, the US Food and Drug Administration (FDA) approved a once-daily, fixed-dose combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection. FTC/TDF, initially approved in 2004 to treat HIV in combination with other antiretroviral agents, became the first drug to be approved to prevent HIV infection in people who are at high risk for infection.1 In May 2014, the US Public Health Service (USPHS) released a set of clinical practice guidelines for PrEP. 2

The FDA approved FTC/TDF for PrEP on the basis of 2 large, randomized, double-blind, placebo-controlled trials.1,3,4

One, the iPrEX (Preexposure prophylaxis initiative) study, was conducted among 2499 HIV-negative men and transgender women who have sex with men. Participants received FTC/TDF or placebo once daily along with HIV testing, risk-reduction counseling, condoms, and treatment for sexually transmitted infections (STIs). After a median 1.2 years of follow-up, 100 participants were found to have acquired HIV infection: 36 in the active prophylaxis group and 64 in the placebo group. This result amounted to a significant 44% reduction in the incidence of new HIV infections among the participants receiving PrEP.3 While demonstrating the efficacy of PrEP, the study also showed the importance of adherence to the regimen. That is, study participants in the active arm who became infected were found to have low levels of FTC/DTF in their blood.3

The other study, called Partners PrEP, was conducted among 4758 serodiscordant heterosexual couples (couples in which 1 partner was HIV-positive and the other was HIV-negative) in Kenya and Uganda. The HIV-negative partners in this study received FTC/TDF, TDF alone, or placebo. A total of 82 of the HIV-negative partners became infected with HIV during the study. Compared with placebo, there was a 67% reduction in the incidence of infection among participants who received TDF alone, and a 75% reduction with FTC/TDF. Both of these results were statistically significant.4

The 2014 USPHS guidelines are based on these studies plus a number of others. Among the most important were the TDF2 Study and the Bangkok Tenofovir Study.5

The TDF2 Study evaluated PrEP in heterosexual men and women in Botswana. The 1219 participants (48% women, 52% men) were randomly assigned to FTC/TDF or placebo with monthly follow-up and prevention services including HIV testing, risk-reduction and adherence counseling, and management of STIs, as well as monitoring for potential drug side effects. Compared with placebo, PrEP reduced the risk of HIV infection by 62%. Again, efficacy correlated strongly with adherence as measured by drug levels.6

The Bangkok Tenofovir Study evaluated PrEP among a group of injection drug users (IDUs) in Thailand, a population that had not previously been studied as candidates for PrEP. The 2413 participants were assigned to receive either TDF or placebo along with monthly HIV testing, risk-reduction and adherence counseling, and safety assessments, and were offered condoms and methadone treatment. Compared with placebo, TDF reduced the risk of HIV infection by 49%. Once again, efficacy was correlated with adherence: among patients with detectable TDF in their blood, the reduction in risk of HIV infection was 74%.7

The USPHS guidelines are based on the premise that daily oral PrEP with FTC/TDF has been proven safe and effective at reducing the risk of becoming infected with HIV through sex with an infected partner. The guidelines recommend PrEP as 1 prevention option for sexually active adults who are at high risk for HIV infection based on their sexual practices. This includes gay and bisexual men, heterosexual men and women, and members of serodiscordant couples. The guidelines note that the safety and efficacy of PrEP for adolescents has not been fully characterized, so clinicians should weigh the risks and benefits of PrEP in counseling adolescent patients.2

Before prescribing PrEP to an eligible patient, clinicians must rule out current HIV infection. PrEP should be prescribed for daily use; the USPHS does not recommend PrEP for so-called coitally-timed or other noncontinuous use. Once a patient has initiated PrEP, the prescribing physician should test for HIV infection at least every 3 months. It is important for patients who acquire HIV infection while on PrEP to discontinue the medication, as the 2-drug FTC/TDF regimen is not sufficient treatment for HIV infection and its continued use may lead to viral resistance to 1 or both drugs.2

Before patients initiate PrEP, clinicians should assess renal function and test for hepatitis B virus (HBV) infection. Impaired renal function and loss of bone mineral density are potential safety concerns with the use of FTC/TDF. It is also important for clinicians to know if a patient is co-infected with HBV as FTC/TDF can be used to combat HBV, and discontinuation of HBV therapy may not be advisable. Clinicians should not prescribe FTC/TDF to any person with an estimated creatinine clearance rate (CrCL) of < 60 mL/min. In patients on PrEP, clinicians should assess renal function at least every 6 months so that patients who develop renal failure do not continue to take PrEP.2

As reflected in the clinical trial data, a high level of adherence is important for the success of PrEP but was not always achieved by participants in trials. Consequently, patients on PrEP should be encouraged to use PrEP in combination with other effective prevention methods (including condoms) and should be provided with access to such methods (directly by the prescribing clinician or via referral to appropriate risk-reduction services).2

Finally, a French study termed Ipergay has shown the success of an approach termed “PrEP on demand,” in which individuals at risk for acquisition of HIV were prescribed FTC/TDF only on the day of anticipated sexual relations and for 2 days thereafter instead of every day. The advantage of the latter approach is that it may lower the side effects associated with FTC/TDF since some patients would be taking fewer pills that once daily. This would also help reduce costs.8 As previously mentioned, however, the USPHS does not sanction this approach.

The complete USPHS Clinical Practice Guidelines for PrEP and A Clinical Provider’s Supplement are available online.The supplement includes a patient checklist to help maximize the benefit of PrEP and informational patient handouts. It also includes a risk measurement tool for MSM, allowing physicians to identify those patients at highest risk for HIV infection for whom PrEP may be indicated. Information about adherence and risk-reduction counseling is also provided, as well as information on administrative and billing codes for PrEP-related services.

The Evolution of HIV Management


Before the development of antiretroviral therapy (ART), before the human immunodeficiency virus (HIV) was identified as the virus that caused AIDS, and before AIDS was recognized as a discrete medical syndrome, there were reports of unusual and inexplicable outbreaks of conditions that were usually associated with immune compromise. These included conditions such asPneumocystis carinii pneumonia (PCP) and Kaposi’s sarcoma (KS), both observed in cohorts of gay men in the summer of 1981. The constellation of opportunistic diseases associated with immune deficiency in otherwise healthy gay men came to be called Gay-Related Immune Deficiency (GRID). Subsequently, the same type of deficiency was observed in other groups, including injection drug users, blood transfusion recipients, hemophiliacs, and Haitian immigrants, as well as infants and the female sexual partners of affected men. Because the condition clearly was not gay-specific, public health officials changed its designation to Acquired Immune Deficiency Syndrome (AIDS). It appeared to be sexually transmitted, but causality initially was unknown.

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In addition to PCP and KS, other opportunistic infections (OIs) were soon observed, including mycobacterial infections, toxoplasmosis, invasive fungal infections, and non-Hodgkin’s lymphoma.1 Treatments were available for some OIs, including PCP2 and KS,3but not for others; for example, in the case of cryptosporidiosis, the only available treatment was palliative therapy with antimotility agents that were not consistently effective.2

Beginning in 1989, the US Department of Health and Human Services (DHHS) issued a series of guidelines for preventing common OIs, including PCP and Mycobacterium avium complex (MAC).2 By 1995, these guidelines covered the prevention of all HIV-related OIs.2

By the early 1990s, advances in OI management led to improved quality of life and increased survival among people with HIV/AIDS. However, it was only with the widespread use of ART, beginning in the mid-1990s, that HIV infection became a chronic, manageable condition. A dramatic reduction in OI-related morbidity and mortality has been observed among patients who have access to ART.2

The road to widespread and effective ART treatments was a winding one. Once HIV, a retrovirus, was identified as the causative agent of AIDS in 1983, the race was on to find effective antiretroviral therapies targeting 1 or more stages in the HIV lifecycle.4 The first target to be effectively exploited was the HIV reverse transcriptase (RT), an enzyme responsible for converting viral RNA into DNA within an infected cell.5 The first nucleoside reverse transcriptase inhibitor (NRTI) was zidovudine (ZDV), approved by the US Food and Drug Administration (FDA) in 1987. Over time, clinical trials showed a survival benefit with ZDV monotherapy in patients with symptomatic HIV infection, but not in asymptomatic infection.6 Moreover, any survival benefit was measured in months rather than years, due to the emergence of viral resistance to the drug.6

The first combination to show a survival benefit in both symptomatic and asymptomatic patients was ZDV/3TC.9 Nevertheless, dual combination therapy with NRTIs, like NRTI monotherapy, proved to be limited by the emergence of resistance.

The turning point came in 1996, with the emergence of 2 new classes of antiretroviral agents. The protease inhibitors (PI) targeted HIV protease, an enzyme responsible for processing viral polyproteins essential to viral maturation.1 Nonnucleoside reverse transcriptase inhibitors (NNRTIs), like the NRTIs, target HIV RT, but via a different mechanism of action. At the XI International AIDS Conference in Vancouver in July 1996, attendees were astounded by the presentation of results from clinical trials of triple-combination therapy, using dual-NRTI “backbones” in combination with a “third agent,” that was either a PI or an NNRTI. These triple-combinations regimens were considerably more potent than dual-NRTI therapy and were referred to as maximally suppressive regimens or highly active antiretroviral therapy (HAART). In addition to the clinical benefit provided, by eliminating detectable virus from the peripheral blood, these regimens delayed or prevented the emergence of drug-resistant viruses, increasing the durability of treatment.

At first, the data from clinical trials favored PI-based regimens over NNRTI-based regimens.11. When DHHS issued the first guidelines for ART in April 1998, the preferred approach to therapy was to combine one of the available PIs (indinavir, nelfinavir, saquinavir, or ritonavir) with an appropriate dual-NRTI backbone. These included ZDV/ddl, d4T/ddl, ZDV/ddC, ZDV/3TC, and d4T/3TC.1.

By the end of 1998, the newly approved NNRTI efavirenz was included among the list of preferred third agents.12. Subsequently, ddI/3TC was added to the list of preferred NRTI backbones and ddC came off the strongly recommended list because of toxicity.13 Studies also showed that ddC did not combine well with other available NRTIs, and it was subsequently withdrawn from the market.14

In the ensuing years, pharmacologic boosting of PIs with subtherapeutic doses of ritonavir, a potent inhibitor of the cytochrome P450 pathway, became routine. Lopinavir (LPV), approved by the FDA in 2000, was the first PI to be coformulated with ritonavir (LPV/r, the small “r” being used to indicate subtherapeutic doses of ritonavir as a pharmacologic booster).

The 2003 recommendations were simplified but gave clinicians more choices in mixing and matching elements of the NRTI backbone. Preferred NNRTI-based regimens included efavirenz plus 3TC combined with ZDV, d4T, or tenofovir disoproxil fumarate (TDF), the first nucleotide RTI, approved by the FDA in 2001. Preferred PI-based regimens included LPV/r combined with 3TC and either ZDV or d4T.15 In 2004, a new NRTI, emtricitabine (FTC), approved by the FDA in 2003, was recognized in the guidelines as interchangeable with 3TC,16 of which it was a fluorinated derivative.17 At the same time, d4T was demoted from preferred to alternative status due to increasing reports of d4T-related toxicities.16

Beginning with the October 2006 guidelines, the preferred dual-NRTI backbones were the coformulated forms of TDF/FTC and ZDV/3TC.18.

In January 2008, another coformulated dual-NRTI backbone joined the preferred list: abacavir (ABC)/3TC. The FDA approved ABC in 1998. Coformulated ZDV/3TC moved from the preferred list to the alternative list, largely because of ZDV-related toxicity. The preference for ABC/3TC, however, was short-lived, as the November 2008 edition of the guidelines listed only TDF/FTC as preferred. ABC/3TC became an alternative because of data showing a higher rate of virologic failure in patients who initiated treatment with an ABC/3TC-containing regimen with a baseline HIV RNA level (viral load) of >100,000 copies/mL in a study termed ACTG 5202.19 Also concerning were data from multiple studies suggesting an association between ABC use and elevated risk for cardiovascular disease, even though there is still no consensus that such an association truly exists.19

The first HIV integrase strand transfer inhibitor (INSTI), raltegravir (RAL), was approved by the FDA in 2007. HIV uses the integrase enzyme to integrate viral DNA into the DNA of infected cells, an essential step in HIV replication.20 Two more INSTIs were approved in 2012 (elvitegravir, EVG) and 2013 (dolutegravir, DTG). EVG needs to be pharmacologically boosted by a newly developed boosting agent termed cobicistat (cobi).

Since 2009, the guidelines have recommended complete regimens, moving away from the idea of recommended dual-NRTI backbones and recommended PIs, NNRTIs, or INSTIs presented in a mix-and-match format. The currently recommended regimens include 4 INSTI-based regimens: DTG/ABC/3TC (coformulated); DTG plus TDF/FTC (the NRTI backbone is coformulated); RAL plus TDF/FTC (the NRTI backbone is coformulated), and EVG/c/TDF/FTC (coformulated; the lower-case c indicates the use of cobi). Also included is one boosted-PI–based regimen, DRV/r plus TDF/FTC (the NRTI-backbone is coformulated; the lower-case r indicates the subtherapeutic dose of ritonavir used for pharmacologic boosting).

Managing Patients with HIV Virologic Failure: Key US Guideline Updates


The US Department of Health and Human Services has revised its guidelines on the management of virologic failure, and a summary of key updates is provided here. The guidelines now include treatment recommendations for (1) virologic failure in various clinical scenarios involving first-line and second-line antiretroviral regimens and (2) isolated central nervous system (CNS) virologic failure with the onset of new neurologic symptoms.1 The complete guidelines are available on the AIDSinfo website at http://www.aidsinfo.nih.gov.

Virologic failure after first-line antiretroviral therapy

Failure of NNRTI plus NRTI modality: Viral resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) component of a regimen, with or without resistance to the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and emtricitabine, is common in patients whose NNRTI-based regimen fails. Recent studies suggest that patients in these cases often may be treated with a pharmacokinetically boosted protease inhibitor (PI), such as lopinavir/ritonavir or darunavir/ritonavir, in combination with NRTIs or the integrase strand transfer inhibitor (INSTI) raltegravir. Other possible choices in this setting include the second-generation NNRTI etravirine or other INSTIs (ie, elvitegravir or dolutegravir) in conjunction with a pharmacokinetically boosted PI, although data on clinical effectiveness are limited.1

Failure of a pharmacokinetically boosted PI plus NRTI modality: Most patients who fail a regimen consisting of a pharmacokinetically boosted PI plus NRTIs will not have resistance mutations for the PI and resistance is likely to be limited to lamivudine and emtricitabine. Virologic failure is usually related to poor adherence or drug-drug or drug-food interactions. If the regimen is well tolerated and no drug-drug or drug-food interaction concerns are apparent, this modality can be continued with compliance support and viral load monitoring. If drug intolerance or adverse interactions may possibly be contributing to virologic failure, the modality may be modified such that a new regimen includes two fully active NRTIs without a PI or a different pharmacokinetically boosted PI plus NRTIs, even if not all of the NRTIs are fully active.1

Failure of an INSTI plus NRTI modality: A combination of raltegravir plus two NRTIs or the four-drug combination of elvitegravir, cobicistat (a cytochrome P450 enzyme inhibitor), emtricitabine, and tenofovir disoproxil fumarate (a NRTI) may lead to virologic failure due to resistance to the NRTI (ie, lamivudine or emtricitabine) and possibly to the INSTI. Based on data extrapolation regarding NNRTI failures, a pharmacokinetically boosted PI plus NRTIs may yield responses in patients with first-line INSTI failures. For those with no INSTI resistance, a pharmacokinetically boosted PI plus an INSTI may be a feasible alternative. When raltegravir and elvitegravir resistance, but not dolutegravir resistance, is observed, dolutegravir may be combined with a pharmacokinetically boosted PI in a subsequent regimen. Patients in whom no resistance is identified should be managed according to previously existing US guidelines for patients experiencing virologic failure with no resistance.1

Virologic failure after second-line antiretroviral therapy

Agents to be used in subsequent regimens should be selected according to predictors of complete virologic suppression, including the patient’s treatment history, results of previous and present drug-resistance testing, as well as tropism testing when a CCR5 antagonist is being considered as a treatment option.1

No consensus recommendations are available for optimal treatment strategies in patients unable to achieve complete virologic suppression due to multidrug resistance. In this clinical setting, antivirals are utilized to maintain immunologic function, impede disease progression, and minimize an increase in resistance to the same or other drug classes, so that as many antiretroviral agents as possible, including possibly some still in development, will be active and useful in future regimens. NNRTIs, as well as enfuvirtide (a fusion inhibitor), elvitegravir, and raltegravir should usually be discontinued if resistance to these antivirals becomes apparent, since most evidence shows they will no longer be able to hinder disease progression. In fact, continuing these agents may lead to selection of additional mutations, leading to higher-level resistance and within-class cross-resistance, thus limiting future treatment alternatives.1

“The stakes are high,” notes Christine Durand, MD, Assistant Professor in the Departments of Medicine and Oncology at the Johns Hopkins University School of Medicine, Baltimore, MD. “With repeated treatment failure, HIV can become resistant to multiple classes of antiretroviral drugs….This could lead to disease progression and death in the individual patient and, if this ‘superbug’ is transmitted to others, then it can become a public health problem, as well.”

Isolated CNS virologic failure

In rare instances, patients experience new onset neurologic symptoms with HIV infection breakthrough in the CNS, despite suppressed viral load.1 Although this condition, referred to as neurosymptomatic cerebrospinal fluid (CSF) escape, is uncommon, it is essential to identify it clinically so that its management and the implications therof can be addressed.2 MRI brain imaging is needed to document encephalitis and to reveal other abnormalities, including variable lesions typically presenting in the white matter.2 In addition, CSF analysis is also critical to detect and evaluate various CSF abnormalities, such as the characteristic lymphocytic pleocytosis. The differential diagnosis of isolated CNS virologic failure should include other CNS infections that may temporarily increase CSF HIV RNA levels, such as herpes zoster, chronic neurocognitive disorders without CNS HIV breakthrough commonly reported in HIV-infected patients, and mild, incidental increases in CSF HIV RNA levels in the absence of neurologic symptoms. Modification in antiretroviral therapy is not currently recommended for these other conditions.1

Experts recommend CSF HIV drug-resistance testing to guide treatment alternatives, considering CNS pharmacokinetics and principles recommended for plasma HIV RNA resistance. If such testing is unavailable, clinicians should modify the regimen based on the patient’s treatment history and predicted drug CNS penetration.1

“The most important goal is to suppress HIV systemically,” Dr. Durand comments. “If there are persistent neurocognitive deficits, referral to a neurologist with HIV expertise would be important. She adds, “Adjunctive neurological and psychiatric medications may provide benefit.”

A complex undertaking

As US guidelines continue to emphasize, an understanding of the underlying cause of virologic failure and determining the best course of action when modifying antiretroviral regimens often necessitate consultation with specialists.1 Optimal management of treatment-experienced patients requires, first and foremost, a thorough analysis of the possible contributing factors to failed antiretroviral therapy, including suboptimal adherence, adverse effects, drug intolerance, comorbidities, drug-drug and drug-food interactions, absorption issues, and psychosocial factors. Also essential are assessments of treatment history, viral load and CD4 count trends, as well as previous and current drug-resistance test results.1“Evaluating the potential reasons for failure and making a plan to address them,” explains Dr. Durand, “require expert knowledge in antiretroviral side effects, pharmacokinetics, and antiretroviral drug resistance, as well as a good understanding of the stigma and psychosocial issues faced by this patient population.”

New Standards of Care in HIV: Immediate Treatment for All


In the United States (US), an estimated 1.2 million people are living with HIV, the virus that causes acquired immune deficiency syndrome (AIDS), and there are some 50,000 new infections annually. Worldwide, there were 37 million people living with HIV in 2014, and 2 million new infections, as well as 1.2 million deaths from AIDS-related conditions.1Since the approval of zidovudine as the first antiretroviral drug (ARV) in 1987, standards of care for HIV have continuously evolved regarding what therapy to initiate and when to start.

“Over the course of 30 years of antiretroviral therapy (ART), we in the US have incrementally increased the number of people who are eligible for treatment until we finally reached universal eligibility,” says Benjamin Young, MD, PhD, Vice President and Chief Medical Officer of the International Association of Providers of AIDS Care (IAPAC), assistant clinical professor of medicine at the University of Colorado, and adjunct professor at the Korbel School of International Studies at the University of Denver. “Now the rest of the world is beginning to embrace that same standard. That is a historic step on the path toward ending the worldwide HIV/AIDS pandemic.”

When the first federal guidelines were published in the US for initiating ART in patients with HIV, the recommendation was to treat symptomatic patients regardless of their CD4 cell count or HIV RNA viral load.2 Asymptomatic patients with CD4 counts below 500 cells/mm3 were to be offered treatment, but treatment was not specifically recommended. And for asymptomatic patients with CD4 counts above 500 cells/mm3, the guidelines gave the clinician the choice between offering treatment and watchful waiting.2

The recommendations for when to start ART in those early days had much to do with the potential risks of therapy, including tolerability, convenience, and long-term safety.2 For a time, concerns about the risks associated with ART drove treatment guidelines in an even more conservative direction. By 2001, the CD4 count cutoff for definitely recommending initiation of treatment in asymptomatic patients was lowered to 200 cells/mm3, and asymptomatic patients with greater than 350 cells/mm3could be offered treatment–but it was not standard of care.3

An important change occurred in 2007, when the recommendation was made to treat asymptomatic patients with CD4 counts below 350 cells/mm3. While there were no data from randomized trials to definitively address the best time to start treatment in asymptomatic patients, several large, long-term observational cohort studies lent support to the recommendation for starting treatment at 350 cells/mm3.4 By the end of 2009, the guidelines recommended ART for patients with CD4 counts between 350 and 500 cells/mm3, but experts were divided on the strength of the evidence.5

Then, in 2012, the recommendation was expanded to initiate ART in all HIV-infected individuals, including asymptomatic patients with CD4 counts greater than 500 cells/mm3.6The expert panel that produced the guidelines based this recommendation not on data from randomized trials but on the growing body of evidence that uncontrolled HIV replication may lead to numerous non-AIDS–defining conditions, including heart, liver, and kidney complications, neurologic complications, and cancers. Also taken into account were the increased efficacy, convenience, and tolerability of newer ART regimens. Finally, a single observational cohort study, the NA-ACCORD study, showed a survival benefit in patients who started treatment at CD4 counts above 500 cells/mm3.6

This indeterminacy around the benefits of immediate therapy for all patients, however, was resolved definitively in 2015, with the publication of results from the START7 and TEMPRANO8 studies. These were both randomized, controlled trials that demonstrated the superior benefit of starting ART at CD4 counts above 500 cells/mm3 compared to any lower CD4 cell count threshold. While these study results did not change the recommendations currently in place, they allowed the strength of the recommendation to be changed from BIII (moderate and based on expert opinion) to A1 (strong and based on data from randomized, controlled trials).9

In the years since the HIV Prevention Trials Network (HPTN) 052 study demonstrated that early initiation of ART not only has clinical benefits for the treated individual, but also dramatically reduces HIV transmission to uninfected sexual partners, public health officials worldwide have embraced a treatment-as-prevention model that relies on early initiation of ART in infected persons for maximum prevention benefit.10 The treatment-as-prevention model gained further credibility from the START and TEMPRANO trials by demonstrating that treatment-as-prevention does not advance prevention objectives at the expense of clinical benefit to the treated patient. In fact, immediate initiation of ART in infected individuals, regardless of CD4 cell count at time of HIV diagnosis, is the best approach for both treatment and prevention.

“Now that we have the final data from HPTN 052, the main takeaway is that we have not seen a single documented case of transmission from an undetectable HIV-positive patient to an HIV-negative sexual partner in hundreds of thousands of encounters, many of them without condoms,” said Dr. Young. “That is an unprecedented achievement and a major incentive to operationalize the policy of universal treatment.”

The WHO joined the US in adopting a recommendation of immediate ART for all HIV-infected patients, announcing its new policy in a September 30 press release.11 Also included in the new WHO guidelines is a recommendation that people at high risk for becoming infected with HIV should be offered pre-exposure prophylaxis (PrEP). Previously, the WHO had recommended PrEP only for men who have sex with men. Now, the recommendation is expanded to other high-risk groups.11 The US Public Health Service issued a similar recommendation in 2014.12

“What these studies [START, TEMPRANO, and HTPN 052] mean and what these two important policy statements [by DHHS and WHO] say is that we now know categorically and with the highest level of scientific certainty that ART is safe and effective as both treatment and prevention, that treatment is prevention, and that treatment prevents deaths, AIDS-defining and non-AIDS–defining illnesses, and cancers, while also preventing transmission from infected patients to uninfected sexual partners,” said Dr. Young.

The changing standard of care for HIV has been driven by a combination of drug development, clinical evidence about the benefits of therapy, and clinical data on the impact of treatment on prevention. The Joint United Nations Programme on HIV/AIDS (UNAIDS) has adopted an ambitious set of goals to end the HIV/AIDS epidemic, called the 90-90-90 treatment target: by 2020, 90% of people living with HIV will know their status; 90% of all people who know their HIV status will be on ART; and 90% of patients on ART will have maximal viral suppression, usually referred to as undetectable viral load.13 Of course, immediate treatment for all and the 90-90-90 treatment targets are goals that will require both financial resources and political will, both in the US and worldwide. And the first of these goals will require that HIV testing becomes far more widely available than is the case at present–and that all those who are at risk for acquisition of HIV be tested on a regular basis.

10 Things to Know About NRTI Dual Backbone Therapy


Dual nucleoside reverse transcriptase inhibitors (NRTIs) consist of two coformulated, fixed-dose tablets that prevent HIV viral replication by blocking the activity of HIV reverse transcriptase–an enzyme that converts viral RNA to DNA within an infected cell. Combining NRTIs has a more potent effect and may increase adherence to HIV treatment regimens when compared to the activity of any single NRTI.1,2

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According to the U.S. Department of Health and Human Services (DHHS), all currently recommended and alternative regimens for antiretroviral therapy (ART) consist of two NRTIs plus a third active drug. The third active drug can include: an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer. Thus, NRTI backbone therapy remains a key component of anti-retroviral therapy (ART) for most HIV-infected patients.3

Here are 10 things that are essential to know when making treatment decisions about NRTI dual backbone therapy:

1. The two currently recommended dual-nucleoside combinations used in initial therapy are abacavir/lamivudine (ABC/3TC) and tenovir/emtricitabine (TDF/FTC).

The DHHS recommends these two NRTI combinations based on the efficacy and durability of virologic response, toxicities, and ease-of-use.3

2. Virologic efficacy has been shown to be comparable in ABC/3TC and TDF/FTC combinations

The HEAT study demonstrated in 688 patients that virologic efficacy is comparable with both ABC/3TC and TDF/FTC NRTI dual backbone regimens. All patients also received LPV/r (a protease inhibitor, where “r” denotes pharmacokinetic enhancement with ritonavir) as a third medication. In a subgroup analysis in patients with HIV RNA ≥100,000 copies/mL, the proportion of patients who achieved HIV RNA <50 copies/Ml was not significantly different at 96 weeks.4The rate of virologic failure was shown to be similar for both groups (14%).4

3. The ASSERT study showed ABC/3TC to be virologically inferior to TDF/FTC

The ASSERT study was designed to compare ABC/3TC and TDF/FTC NRTI backbone therapies in 385 antiretroviral therapy-naive, HLA B*5701-negative patients. All patients also received efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor. Renal safety, as measured by estimated glomerular filtration rate (eGFR) of both regimens, was assessed.5

While there was no difference in treatment groups in renal function, the results demonstrated that at week 48, the TDF/FTC-treated group had a higher proportion of patients with HIV RNA <50 copies/mL compared with patients treated with ABC/3TC.5

4. ABC/3TC is not recommended when viral RNA is ≥100,00 copies/mL

The ACTG 5202 study was a randomized, controlled trial designed to compare the efficacy and safety of ABC/3TC with TDF/FTC, used with either the NNRTI efavirenz or the protease inhibitor atazanavir (ATV/r).6At screening, randomization was stratified by HIV RNA level: either <100,000 copies per/mL or ≥100,000 copies/mL.6

The study demonstrated that time to protocol-defined virologic failure was significantly shorter in the ABC/3TC arm compared to the TDF/FTC arm in patients with ≥100,000copies/mL. This effect was seen regardless of the third active drug that was used.6,7

There was no difference in time to virologic failure in the group with HIV RNA levels <100,000 copies per/mL.7

5. ABC NRTI backbone therapies should only be considered in patients who are HLA B*5701 negative

Before the use of HLA-B* 5701 testing was standard, 5% to 8% of patients treated with ABC experienced hypersensitivity reactions. Patients who are positive for the HLA-B*5701 allele are at high risk for hypersensitivity reactions, and testing for this allele should precede initiation of ABC-based therapy.8,9

Therefore, current DHHS guidelines recommend that only HLA-B* 5701-negative patients should be initiated with ABC/3TC dual backbone therapy.3

6. Use of ABC as part of dual NRTI therapy should proceed with caution in patients with known cardiovascular risk

The initial report of an association between ABC use and myocardial infarction (MI) came from the D:A:D study. This large, multinational observational study group found that patients who were currently using or had used ABC within the previous 6 months were at increased risk of MI. The risk was increased in patients who had other cardiac risk factors.10

Subsequent to the D:A:D report, there have been conflicting results regarding the association between cardiovascular risk and ABC-based backbone therapy, with only some studies having confirmed CV risk.1113Other studies have failed to establish an association.1416

Based on conflicting evidence, the DHHS recommends avoiding ABC/3TC backbone therapy or using it with caution in patients with cardiovascular risk factors.3

7. NRTI dual backbone therapycan be associated with mitochondrial dysfunction, particularly with the “d” NRTIs [didanosone (ddI) and stavudine (d4T)].

Mitochondria have their own DNA with 16,000 bases; the replication, recombination and repair of mitochondrial DNA (mtDNA) is achieved by human gamma-polymerase.17 In addition to impairing HIV replication, NRTIs also inhibit human gamma-polymerase. This results in the decline or depletion of mtDNA, resulting in mitochondrial toxicity and associated mitochondrial disorders.17

MtDNA depletion is both time and dose-dependent, with the “d” NRTIs (ddI, d4T, and zalcitabine [ddC], which are rarely used) having the highest affinity to inhibit gamma-polymerase.

In fact, ddI and d4T are not currently recommended as dual NRTI backbone therapy due to a high incidence of toxicities, in particular peripheral neuropathy, pancreatitis and lactic acidosis. In addition, ddI and TDF are not recommended in combination due to a synergistic increase in ddI concentrations—leading to increased risk of pancreatitis and lactic acidosis.3

NRTI mitochondrial toxicity can accumulate in various tissues and can include the following manifestations:17 hepatotoxicity (increased lipid deposits in the liver, which can be associated with micro or macrovasular steatosis and elevated liver transaminases. In rare cases, steatohepatatitis can progress to liver failure and lactic acidosis); elevation in serum lactate; mitochondrial myopathy (manifested as skeletal weakness); cardiomyopathy; peripheral neuropathy; lipodystrophy (can lead to insulin resistance and hypercholesterolemia); pancreatitis; lymphopenia and anemia; impaired ATP production may elevate serum urate production; renal dysfunction; osteopenia.

8. Use TDF/FTC to treat HIV/hepatitis B (HBV) coinfection

TDF, FTC, and 3TC are active against both HIV and HBV. The use of TDF /FTC or TDF/3TC is recommended wherever possible in patients who are coinfected with HBV and HIV.3

9. FTC and 3TC Have similar resistance profiles and are not recommended as dual NRTI backbone therapy

These two NRTI drugs have been shown to have minimal additive effects and have similar resistance profiles. Therefore, the benefit of decreased risk of resistance with dual therapy is lost with this combination.3

10. Stavudine (d4T) and zidovudine (ZDV) have demonstrated antagonism in combination both in vivo and in vitro

Patients receiving ZDV in combination with d4T showed progressive declines in CD4 cell counts. By 16 weeks, there was a median of 22 cells/mm3. Intracellular levels of d4T-triphosphate in 6 patients were consistent with in vitro studies that demonstrated antagonism between d4T and ZVD.

Insights on the Pathogenesis of Neurocognitive Impairments in the Era of Combined ART


Neurocognitive disorders are well-recognized complications of the human immunodeficiency virus (HIV) and significant cognitive, behavioral, and motor impairments are due to central nervous system (CNS) damage caused by the virus.1 Patients aged 50 years and older are at greatest risk of development of HIV-associated neurocognitive disorders (HAND),1 and aging can exacerbate the progression of HIV disease.2

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The three Frascati criteria provide a classification system that reflects the severity and impact of HAND on daily life; patients may experience asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD).3,4 Reduced adherence to medical therapy, impaired ability to perform complex daily tasks, decreased quality of life, lost work productivity, increased risk of dementia, higher rates of virologic failure, and death are all potential consequences of even the mildest form of HAND.13

The effects of HIV on the CNS changed dramatically when combination antiretroviral therapy (cART) became the standard of care.3 Rates of HAD declined as a consequence while the prevalence of ANI and MND increased, with rates ranging from 20% to 50% in treated patients.1,3,4 The goal of cART in patients with HAND is to achieve adequate levels of drug in the CNS while preventing drug-related neurotoxicities.3 Sustained adherence to cART is credited with the reduced incidence of HAD.1 David J. Moore, PhD, Associate Professor of Psychiatry at the University of California, San Diego, HIV Neurobehavioral Research Program, noted that “Treating HIV early is very important to preventing HAND as well as many other HIV-related complications. In my opinion, we need to focus on strategies to identify HIV-infected persons as early as possible and to get those individuals on treatment immediately.”

However, clinicians’ efforts to effectively manage their patients with HAND are challenged by our lack of a clear understanding of the pathogenesis of this neurocognitive complication of HIV. Direct injury (caused by HIV and viral proteins such as gp120, Tat, and Vpr); indirect damage (caused by proinflammatory cytokines); and chronic, sustained immune activation in the CNS all are considered key factors in the pathogenesis of HAND.1,3 It is generally agreed that events secondary to HIV infection are responsible for the majority of CNS damage associated with HAND.3

Proposed explanations for the neurologic damage and development of HAND are based on the assumption that HIV enters the CNS by the migration of monocytes and lymphocytes that cross the blood-brain barrier, a process described as a “Trojan horse” mechanism.1,3 It works like this: Monocytes infected with the virus are transformed into perivascular macrophages that surround perforating arteries and veins in the brain parenchyma.3,5 When the virus replicates, monocyte-derived macrophages and microglia release neurotoxic molecules. These, in turn, activate astrocytes that increase the permeability of the blood-brain barrier, resulting in additional monocyte and lymphocyte penetration.3

Direct injury caused by HIV and viral proteins such as gp120, Tat, and Vpr1,3 combined with indirect damage caused by proinflammatory cytokines and chronic and sustained immune activation in the CNS are considered key factors in the pathogenesis of HAND.1,3 HIV damages the basal ganglia, deep white matter, and the hippocampus of the brain. Imaging studies demonstrate cerebral atrophy, symmetrical white matter lesions, reductions in gray matter volume in the medial and superior frontal gyri, and aging effects in the frontotemporal gray and white matter in HIV-positive patients. CNS cells infected with HIV also release neurotoxic products that cause proximal neuronal death. Neuronal injury is caused by the toxic effects of HIV viral proteins and inflammatory products released by infected CNS cells.1,3

The persistence of HAND despite ongoing cART is attributed to latent reservoirs of HIV and decreased CNS penetration of antiretroviral medications. The virus is thought to remain in CNS tissue despite clinical evidence of viral suppression in the blood, and interruptions in cART can activate these reservoirs.1,5

“Treatment interruptions or sporadic adherence may allow for drug-resistant strains of HIV infection to develop. HIV strains that are not effectively controlled by antiretroviral regimens are likely to have a bigger effect on the brain and HAND,” added Dr. Moore.

Host and disease-related factors, comorbid health conditions, and behavioral factors also contribute to the pathogenesis of HAND. Genetic predispositions, metabolic disorders, aging, vascular disease, anemia, and malnutrition are all thought to increase the risk of HAND. HIV-associated factors involved in the development of HAND include AIDS, immune activation, HIV subtype, neuroadaptation, drug resistance, and CD4+ nadir.3 Daniel Elbirt, MD, Head of the Immunology Service at the Clinical Immunology, Allergy, and AIDS Unit of Kaplan Medical Center in Israel, says that “HAND is a multifactorial disease caused not just by HIV or the inflammation (although these are the main driving forces), but also by the influences of environmental factors such as nutrition, genetics, other infections and comorbidities, lifestyle factors, and more.”

Additionally, substance abuse has detrimental effects on the CNS and co-infection with hepatitis C and HIV is an independent risk factor for HAND.3 Other mental health factors may also come into play. Ned Charlton Sacktor, MD, Professor of Neurology at John Hopkins Bloomberg School of Public Health, emphasized that “depression, substance use, and alcohol use are confounding conditions that can be associated with cognitive impairment in patients with HAND. Effective treatment of depression and eliminating alcohol and illicit drug use can improve cognitive status or help prevent further deterioration.”

Athough treatment with cART reduces the incidence of HAD, antiretroviral therapies also play a role in the pathogenesis of HAND. Antiretroviral therapy effectively targets viral replication and increases T-cell counts, but is less effective for the control of macrophage polarization, brain infection, and inflammation.5 Notably, cART is associated with inflammation in the temporal cortex and hippocampus, which impairs working memory, and increases the production of brain lymphocytes that results in a motor-cognitive disorder similar in presentation to amyotrophic lateral sclerosis.2 Evidence exists of a synergistic effect of HIV and drug abuse on expression of major histocompatibility complex II and CD68 inflammatory markers, which can have a detrimental effect on cognitive function.2

It is also important to recognize the nonequivalence of antiretroviral drugs with respect to their ability to cross the blood-brain barrier. Fat soluble and low molecular weight drugs have a greater ability to cross this barrier compared with agents that tightly bind to plasma proteins.3Recent research by the CHARTER (CNS HIV Antiviral Therapy Effects Research) group established a CNS penetration-effectiveness (CPE) ranking system for antiretroviral medications. Higher CPE scores were associated with significantly lower viral loads in the cerebral spinal fluid (CSF) and a CPE score >7 resulted in a significant reduction in the number of patients with detectable viral load in the CSF. It is not yet clear, however, that antiretroviral regimens with a high CPE reduce the risk of HAND or can prevent or reduce neurocognitive impairment in patients with HIV.3

Dr Elbirt urged his colleagues to “test widely for HIV so we can diagnose individuals with early HIV and immediately start antiretroviral therapy regardless of CD4 count to reduce inflammation as much as possible. As chronic HIV infection seems to be responsible for a kind of accelerated aging, it is very important to monitor patients and aggressively treat other health conditions such as obesity, diabetes, hypertension, and hypercholesterolemia. These are the best ways to prevent HAND until we have better treatment strategies.” A combination of antiretroviral medications with a high CPE is considered the best treatment option for patients with HAND, while efforts to identify adjunctive and alternative therapies are underway

Evolving Treatment Paradigms for Patients With HCV/HIV Coinfection


The development of DAAs for the treatment of HCV infection has ushered in a new era in the treatment of chronic HCV. DAAs target the HCV virus itself, rather than the immune system of the host, leading to improved efficacy and tolerability when compared with older immune-based therapies that had been the standard of care for HCV for more than a decade. The advances associated with these new therapies are especially pronounced in the population of patients coinfected with HCV and HIV.

Because of shared modes of transmission, HCV is common among persons with HIV infection. Among injection drug users, HCV and HIV may have been acquired via injection paraphernalia shared with an infected individual.1 An increased risk for HCV infection via sexual transmission has also been reported among men who have sex with men.2 The successful treatment of HCV in persons coinfected with HIV is of particular importance because progression of HCV-related liver disease has been shown to be accelerated in coinfected individuals.3,4

In view of the data on the increased rate of progression of liver disease among coinfected individuals, current HIV treatment guidelines recommend antiretroviral therapy (ART) for virtually all patients coinfected with HCV/HIV, regardless of CD4 cell count.5 This recommendation is also supported by data suggesting that ART may slow the progression of liver disease by restoring or maintaining immune function.6 The guidelines note that when starting both ART and HCV therapy in a patient, the ART regimen should be selected based on the potential for drug-drug interactions and overlapping toxicities with the HCV regimen. In patients with CD4 cell counts >500 cells/mm3, providers may elect to defer ART until HCV therapy is completed to avoid drug-drug interactions.5

As in HCV-monoinfected patients, the recommended treatment for HCV infection in coinfected patients has long been pegylated interferon/ribavirin. However, this treatment was associated with a poor rate of sustained virologic response (SVR) and significant side effects, resulting in generally low acceptance rates by patients and providers.7,8 Given the lower rates of SVR in co-infected compared with HCV monoinfected patients, the latter have been classified as a “hard-to-treat” population for more than a decade.

The arrival of DAAs has fundamentally changed the treatment of HCV, with dramatically improved SVR rates and substantially better tolerability.9,10 It appears that these improvements are mirrored in the coinfected population. According to the results of recently published clinical trials, the new oral DAA combination regimens provide high SVR rates (> 90%) among coinfected patients and are generally well tolerated.1114 In addition, data from cohorts of HCV/HIV coinfected patients provide confirmation of the efficacy of the DAAs in real-world clinical settings.15,16 In light of these data, Joop E. Arends, MD, from the University Medical Center Utrecht in Utrecht, The Netherlands, highlighted the increasing acceptance of the new regimens among clinicians: “Given the encouraging results of recent DAA trials, most HIV clinicians see HCV treatment as easier and less complicated; therefore, willingness to start therapy in HIV/HCV coinfected patients is increasing.”

Along with the dramatic improvements in efficacy and tolerability, however, treatment with the new DAAs requires careful attention to a variety of complex drug interactions between ART medications and DAAs.10 According to Dr Arends, “Drug-drug interactions are still a problem, even with the new DAAs.” He explained that given current recommendations to initiate combination ART in all patients diagnosed with HIV infection, regardless of CD4 cell count, recommendations for the management of HCV in coinfected patients emphasize the importance of considering how an existing ART regimen is likely to affect the DAA regimen and vice versa.5,17 Moreover, prescribers should check for possible drug-drug interactions between the DAAs and all concomitant medications. The pharmacokinetic interactions among DAAs and ART depend upon the metabolism of the individual agents. DAAs that are metabolized by the CYP450 system can have significant effects on ARTs that are metabolized by (or inhibit or induce) the same pathways. Similarly, DAAs that are substrates of p-glycoprotein (P-gp) may be affected by inducers of P-gp. The interactions for each of the approved agents (along with recommended dosage adjustments) are reviewed thoroughly in HIV and HCV treatment guidelines on the joint American Association for the Study of Liver Diseases/Infectious Disease Society of America HCV guidelines webpage and at theUniversity of Liverpool drug interaction website.5,17

Recent improvements in HCV therapies have resulted in comparable efficacy and tolerability for DAA regimens among HCV/HIV coinfected and HCV-monoinfected patients. With the advent of the DAA regimens, Dr Arends noted, “There is hardly any difference between the 2 populations with respect to side effects or compliance. Both groups behave similarly well with very high SVR rates.” He concluded that given the data, “HCV/HIV coinfected patients are no longer considered a special population.” The most recent treatment guidelines agree and recommend that coinfected patients be treated no differently than monoinfected individuals.

Managing Patients with HIV Virologic Failure: Key US Guideline Updates


The US Department of Health and Human Services has revised its guidelines on the management of virologic failure, and a summary of key updates is provided here. The guidelines now include treatment recommendations for (1) virologic failure in various clinical scenarios involving first-line and second-line antiretroviral regimens and (2) isolated central nervous system (CNS) virologic failure with the onset of new neurologic symptoms.1 The complete guidelines are available on the AIDSinfo website at http://www.aidsinfo.nih.gov.

Virologic failure after first-line antiretroviral therapy

Failure of NNRTI plus NRTI modality: Viral resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) component of a regimen, with or without resistance to the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and emtricitabine, is common in patients whose NNRTI-based regimen fails. Recent studies suggest that patients in these cases often may be treated with a pharmacokinetically boosted protease inhibitor (PI), such as lopinavir/ritonavir or darunavir/ritonavir, in combination with NRTIs or the integrase strand transfer inhibitor (INSTI) raltegravir. Other possible choices in this setting include the second-generation NNRTI etravirine or other INSTIs (ie, elvitegravir or dolutegravir) in conjunction with a pharmacokinetically boosted PI, although data on clinical effectiveness are limited.1

Failure of a pharmacokinetically boosted PI plus NRTI modality: Most patients who fail a regimen consisting of a pharmacokinetically boosted PI plus NRTIs will not have resistance mutations for the PI and resistance is likely to be limited to lamivudine and emtricitabine. Virologic failure is usually related to poor adherence or drug-drug or drug-food interactions. If the regimen is well tolerated and no drug-drug or drug-food interaction concerns are apparent, this modality can be continued with compliance support and viral load monitoring. If drug intolerance or adverse interactions may possibly be contributing to virologic failure, the modality may be modified such that a new regimen includes two fully active NRTIs without a PI or a different pharmacokinetically boosted PI plus NRTIs, even if not all of the NRTIs are fully active.1

Failure of an INSTI plus NRTI modality: A combination of raltegravir plus two NRTIs or the four-drug combination of elvitegravir, cobicistat (a cytochrome P450 enzyme inhibitor), emtricitabine, and tenofovir disoproxil fumarate (a NRTI) may lead to virologic failure due to resistance to the NRTI (ie, lamivudine or emtricitabine) and possibly to the INSTI. Based on data extrapolation regarding NNRTI failures, a pharmacokinetically boosted PI plus NRTIs may yield responses in patients with first-line INSTI failures. For those with no INSTI resistance, a pharmacokinetically boosted PI plus an INSTI may be a feasible alternative. When raltegravir and elvitegravir resistance, but not dolutegravir resistance, is observed, dolutegravir may be combined with a pharmacokinetically boosted PI in a subsequent regimen. Patients in whom no resistance is identified should be managed according to previously existing US guidelines for patients experiencing virologic failure with no resistance.1

Virologic failure after second-line antiretroviral therapy

Agents to be used in subsequent regimens should be selected according to predictors of complete virologic suppression, including the patient’s treatment history, results of previous and present drug-resistance testing, as well as tropism testing when a CCR5 antagonist is being considered as a treatment option.1

No consensus recommendations are available for optimal treatment strategies in patients unable to achieve complete virologic suppression due to multidrug resistance. In this clinical setting, antivirals are utilized to maintain immunologic function, impede disease progression, and minimize an increase in resistance to the same or other drug classes, so that as many antiretroviral agents as possible, including possibly some still in development, will be active and useful in future regimens. NNRTIs, as well as enfuvirtide (a fusion inhibitor), elvitegravir, and raltegravir should usually be discontinued if resistance to these antivirals becomes apparent, since most evidence shows they will no longer be able to hinder disease progression. In fact, continuing these agents may lead to selection of additional mutations, leading to higher-level resistance and within-class cross-resistance, thus limiting future treatment alternatives.1

“The stakes are high,” notes Christine Durand, MD, Assistant Professor in the Departments of Medicine and Oncology at the Johns Hopkins University School of Medicine, Baltimore, MD. “With repeated treatment failure, HIV can become resistant to multiple classes of antiretroviral drugs….This could lead to disease progression and death in the individual patient and, if this ‘superbug’ is transmitted to others, then it can become a public health problem, as well.”

Isolated CNS virologic failure

In rare instances, patients experience new onset neurologic symptoms with HIV infection breakthrough in the CNS, despite suppressed viral load.1 Although this condition, referred to as neurosymptomatic cerebrospinal fluid (CSF) escape, is uncommon, it is essential to identify it clinically so that its management and the implications therof can be addressed.2 MRI brain imaging is needed to document encephalitis and to reveal other abnormalities, including variable lesions typically presenting in the white matter.2 In addition, CSF analysis is also critical to detect and evaluate various CSF abnormalities, such as the characteristic lymphocytic pleocytosis. The differential diagnosis of isolated CNS virologic failure should include other CNS infections that may temporarily increase CSF HIV RNA levels, such as herpes zoster, chronic neurocognitive disorders without CNS HIV breakthrough commonly reported in HIV-infected patients, and mild, incidental increases in CSF HIV RNA levels in the absence of neurologic symptoms. Modification in antiretroviral therapy is not currently recommended for these other conditions.1

Experts recommend CSF HIV drug-resistance testing to guide treatment alternatives, considering CNS pharmacokinetics and principles recommended for plasma HIV RNA resistance. If such testing is unavailable, clinicians should modify the regimen based on the patient’s treatment history and predicted drug CNS penetration.1

“The most important goal is to suppress HIV systemically,” Dr. Durand comments. “If there are persistent neurocognitive deficits, referral to a neurologist with HIV expertise would be important. She adds, “Adjunctive neurological and psychiatric medications may provide benefit.”

A complex undertaking

As US guidelines continue to emphasize, an understanding of the underlying cause of virologic failure and determining the best course of action when modifying antiretroviral regimens often necessitate consultation with specialists.1 Optimal management of treatment-experienced patients requires, first and foremost, a thorough analysis of the possible contributing factors to failed antiretroviral therapy, including suboptimal adherence, adverse effects, drug intolerance, comorbidities, drug-drug and drug-food interactions, absorption issues, and psychosocial factors. Also essential are assessments of treatment history, viral load and CD4 count trends, as well as previous and current drug-resistance test results.1“Evaluating the potential reasons for failure and making a plan to address them,” explains Dr. Durand, “require expert knowledge in antiretroviral side effects, pharmacokinetics, and antiretroviral drug resistance, as well as a good understanding of the stigma and psychosocial issues faced by this patient population.”

‘Bag of Pills’: Is It Necessary?


Polypharmacy is a difficult problem for many physicians who treat older patients, but there are steps they can take to cut down on their patients’ medications,Amit Shah, MD, said here at the American College of Physicians annual meeting.

“I do a lot of medical student and resident teaching, and whenever I teach this topic, I like to say, ‘As a geriatrician, I have cured more disease by stopping medications than starting them,'” said Shah, who is at the Mayo Clinic in Scottsdale, Ariz. “It’s a bit of an overstatement but it gets people’s attention” because they never thought about fixing problems by taking medications away rather than adding things on.”

Shah added that he is not a “nihilist,” and that he likes the fact that physicians have drugs they can offer patients. In addition, he noted that “Underprescribing can be just as much a problem as overprescribing.”
However, there are reasons why some patients get prescribed more drugs than they may actually need, Shah said. One is “prescribing inertia” — the patient is already taking the drug, so when it comes up for a refill, the doctor automatically refills it. Electronic medical records make it amazingly easy to approve a refill, he added.
As an attending physician, “I once almost killed [an 86-year-old] patient who didn’t get killed by their saddle pulmonary embolism (PE) … he had been on four blood pressure medicines prior to admission,” Shah said. At discharge from the intensive care unit, the intern just hit “continue” on the computer four times, and kept all four of the medications going, even though “[the patient’s] heart was not the same heart it was prior to his PE … he goes to the coumadin clinic and his blood pressure was 60 systolic; he was a little woozy! His saddle PE didn’t kill him but me and my intern almost did.”
“If the intern had to write out four new prescriptions like we did once upon a time, he wouldn’t have started the patient on four new blood pressure medications at discharge … This was a systems issue,” Shah said.
Other reasons polypharmacy occur include the assumption that there must be a thoughtful provider behind each prescription, “not wanting to step on the toes” of the original prescribing provider, and patients and providers not wanting to “rock the boat.”

Shah listed his 10 steps for successful medication “debridement”:
Find out all of the medications the patient is taking. The best way to do this is with a home visit, according to Shah. “Make sure you think about things like over-the-counter (OTC) medications.” He cited one study showing that 70% of hospital discharge records had at least one medication reconciliation error when compared with the medications actually taken at home; 30% of these errors were potentially serious.
Assess whether each medication is potentially harmful. There are many drugs for which safer alternatives exist — for example, patients could be prescribed glipizide rather than a long-acting sulfonylurea such as glyburide or glimepiride. There are also several lists of medications — such as the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults and the Screening Tool of Older Person’s potentially inappropriate Prescriptions (STOPP) that physicians may want to consult, Shah said. However, he cautioned that these are not “blacklists” and physicians who do need to prescribe these medications should be wary of insurers trying not to cover them because they are on the list.
Consider whether the drug is actually approved for the indication you’re prescribing it for. Shah noted that about 20% of all prescribing is off-label; for psychiatric drugs, it’s about 40%.
Think about whether the drug has outlived its usefulness for that patient. He compared the way some drugs “attach” themselves to patients with the way Arizona’s jumping cholla plant attaches itself to people. Shah said he asked one patient why he was taking omeprazole. The patient’s response: “It’s for my heart, doc. [I went in for] chest pain, and they gave this to me, and I haven’t had a twinge of chest pain ever since.” Shah then asked the patient if he had ever had heartburn. He said no “and then he told me his recipe for five-alarm chili and proceeded to tell me all the spicy foods he can eat … In the ICU, a lot of patients end up on PPIs [proton pump inhibitors] and they just continue it,” whether it’s necessary or not.
Consider whether a drug’s side effects outweigh its benefits. Shah gave the example of Aricept (donepezil) for dementia and noted that although the results of the clinical trials of the drug were highly statistically significant, the average increase in score on the ADAS cognitive scale for patients on the drug was only 3 points out of 70. The drug does work occasionally for hallucinations and for patients with Lewy body dementia, and that it helps with word-finding difficulties in a few patients. “These medications have a role, but not as much as we think,” Shah said. He noted that the package insert itself says Aricept doesn’t affect the course of the disease, but, 20% of patients taking the drugs had side effects, including bradycardia and increased risk of new-onset urinary incontinence. Also, the brand-name drug costs about $300 per month.
Watch out for drug-drug and drug-disease interactions. “I’m not smart enough to [figure out] all the drug-drug interactions when a patient is on 20 different medications,” said Shah. But an electronic reference such as Epocrates can suggest some drug-drug interactions that may be important to look at. “Electronic medical records are [also] good at this, but we get alert fatigue,” he added.
Look for reactions with any herbal medications or other OTC drugs. For example, calcium supplements decrease absorption of levothyroxine, quinolone antibiotics, and tetracyclines, and “these are clinically significant,” he said. Time of administration can also be a factor: One of Shah’s patients didn’t have a problem with her TSH level until she moved to an assisted living facility at which she was given all her drugs at one time, rather than spacing out her levothyroxine and her calcium supplement, as she had been doing at home.
See if the drug you’re prescribing is being used to treat the side effects of another drug. This problem is known as the “prescribing cascade” — a drug that is prescribed has a side effect, so the physician puts the patient on a second drug to deal with the side effects of the first one, and so on. Shah said he was able to “cure” Parkinson’s disease-like symptoms in a patient with diabetes who began having Parkinsonian-like symptoms after she was put on metoclopramide (Reglan), which had been prescribed for nausea and vomiting. That patient had been put on levodopa by her neurologist, but her symptoms mostly disappeared once the metoclopramide was stopped, Shah said.
Look for a nonpharmacologic approach to try instead of a drug. For example, he said, patients with urinary incontinence can be prescribed scheduled voiding and Kegel exercises. Patients with sleep problems can be counseled about normal changes that occur with sleep during the aging process, and be advised to consider relaxation techniques and napping. Addressing the underlying issues can help — for instance, if a patient is having sleep problems due to pain, prescribe acetaminophen before bedtime rather than Ambien (zolpidem) for sleep.
Think about whether the patient will live long enough to gain a benefit from the drug. Shah gave the example of a 102-year-old patient who was put on a statin for primary prevention after her physician discovered she had hypercholesterolemia. The ePrognosis app can help with this issue by estimating the prognosis for elderly patients, he said.
Being successful in decreasing polypharmacy can be very satisfying, he noted. “It’s really fun when you unwind six to seven medications in your patients, which I’ve done, and they feel better.”