tenofovir

Tenofovir to Prevent Perinatal Transmission of Hepatitis B

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A 36-year-old pregnant woman, originally from Southeast Asia, presents to her family medicine physician for prenatal care in the first trimester. She has had no history of medical problems. On family history, she reports that her mother recently died of liver cancer due to hepatitis B virus (HBV). The patient’s prenatal screening indicates that she is hepatitis B e antigen (HBeAg)-positive, with normal liver function tests. The physician explains to the patient that the blood test showed that she is a chronic carrier of hepatitis B, which she likely got as a baby from her mother. The patient asks, “Are there any new treatments to prevent me from passing hepatitis B to my baby?”

Mother-to-child transmission of HBV is a leading cause of chronic HBV infection and liver cancer worldwide, particularly in Asia. Prior to the availability of perinatal interventions to prevent HBV transmission, mothers with chronic HBV infection had an approximate 1 in 3 chance of passing HBV to their baby during pregnancy, delivery, or infancy; and more than 65%-90% of infected children developed chronic HBV infection.

Over the past few decades, perinatal transmission of HBV has been reduced dramatically by two key interventions: Universal HBV immunization for infants starting at birth, with at least 3 doses by 6 months of age, and administration of hepatitis B immunoglobulin (HBIg) at birth to infants born to HBV-infected mothers. However, for mothers who are HBeAg-positive with high HBV loads (>200,000 IU/mL), perinatal HBV transmission still occurs in up to one third of cases. Researchers have postulated that perinatal administration of antiviral medication could inhibit HBV replication and reduce the risk of perinatal HBV transmission.

This week, NEJM published a multicenter, double-blind, randomized clinical trial conducted in Thailand to test the effectiveness of antiviral medication to prevent perinatal HBV transmission. A total of 331 HBeAg-positive pregnant women with normal liver function tests (ALT ≤60 IU/L) were randomized to receive tenofovir or placebo from 28 weeks of gestation to 2 months postpartum. All infants received HBIg at birth and HBV vaccine at birth and at ages 1, 2, 4, and 6 months. The primary outcome was HBV surface-antigen (HBsAg) positivity, confirmed by HBV-DNA in the infants at 6 months of age.

The results showed that maternal HBV viral load declined substantially in the tenofovir group, with no change in the placebo group; and at delivery, 12% of women in the tenofovir group had elevated HBV DNA levels versus 90% in the placebo group. Among the live-born babies, 0 of the 147 babies in the tenofovir group were HBsAg positive (0%; 95% CI, 0-2), compared to 3 of 147 in the placebo group (2%; 95% CI, 0-6), a nonsignificant difference (P=0.12). Adverse events in mothers and babies did not differ significantly between groups.

The authors concluded that in the setting of low HBV transmission rates, treating pregnant women with tenofovir in addition to administration of infant HBV vaccine and HBIg did not significantly reduce mother-to-child transmission of HBV. However, the small sample size may have limited the study’s ability to demonstrate statistical significance. This study joins a handful of similar studies — some considered low-quality — with conflicting results about whether antiviral treatment significantly reduces perinatal HBV transmission. As a result, expert recommendations have differed (e.g., the 2015 WHO hepatitis guidelines for management of chronic HBV did not recommend antiviral treatment, but the 2016 American Association for the Study of Liver Diseases guidelines did recommend antiviral treatment for pregnant women who were HBsAg positive with high HBV DNA levels). Dr. Lindsey Baden, an infectious diseases specialist and Deputy Editor at NEJM commented, “The benefits of preventing maternal-to-child transmission of HBV are life-long, and we must continue to improve our ability to do this. These data are encouraging, but it will require a substantially larger study to definitively demonstrate additional benefits to current practices.”

Returning to the physician and the pregnant patient, the physician should express sympathy about the patient’s mother’s death and reassure her that they will work closely together in consultation with a liver specialist to try to keep her healthy. The physician should also reassure the patient that the current treatments for babies born to women carrying hepatitis B, which were not available when she was born, can usually prevent hepatitis B from passing from mothers to babies. Because there a low risk of passing hepatitis B to the baby, the physician and patient should discuss whether the patient wishes to take tenofovir.

Antiretroviral PrEP for Injection-Drug Users?

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In a randomized, controlled trial involving injection-drug users in Thailand, tenofovir reduced the risk for HIV infection.

 

Antiretroviral pre-exposure prophylaxis (PrEP) is effective in preventing sexually acquired HIV infection among men who have sex with men as well as heterosexual men and women. Might it also help to prevent HIV infection among injection-drug users? To find out, investigators from the CDC and the Thailand Ministry of Health conducted a study involving HIV-uninfected injection-drug users recruited at drug-treatment clinics in Bangkok.

A total of 2413 individuals were randomized to oral tenofovir or placebo, either administered daily via directly observed therapy (DOT) or provided at monthly visits. The decision to use DOT was up to the participants, who could switch at monthly visits. Each month during follow-up (mean duration, 4 years), participants received HIV testing and risk-reduction and adherence counseling. Drug levels were also measured at some of the clinics, and at the time of the first positive HIV test in all individuals who seroconverted.

The median age of participants was 31; 80% were men, and 48% had 

≤6 years of education. Twenty-two percent were enrolled in a methadone program. Baseline characteristics were similar between groups, except that sexual intercourse with casual partners and having sex with men during the 12 weeks preceding enrollment were more common in the placebo group.

HIV infection was confirmed in 50 participants — 17 in the tenofovir group and 33 in the placebo group — for an overall 48.9% reduction in HIV incidence with tenofovir in intent-to-treat analysis. Efficacy was higher — 73.5% — among individuals with detectable tenofovir levels in their plasma.

Comment: This study is the first to demonstrate the efficacy of tenofovir in preventing HIV infection among injection-drug users. Almost concomitantly, the CDC published interim guidance for pre-exposure prophylaxis in this population. Interestingly, the CDC recommended using tenofovir/FTC (not tenofovir alone, as studied in Thailand), arguing that tenofovir/FTC and not tenofovir alone is approved by the FDA for prophylaxis. The CDC also suggested that prevention services targeting injection and sexual risk behaviors be provided for injection-drug users.

I must emphasize that this study used directly observed therapy as one strategy, and that efficacy of antiretrovirals for prevention depends on adherence. Thus, any PrEP program should incorporate strong adherence counseling.

 

Source: Journal Watch HIV/AIDS Clinical Care

HIV pre-exposure prophylaxis in injecting drug users.

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Globally, there are an estimated 15·9 million injecting drug users, 3 million of whom have HIV.1 The illicit nature of injection drug use and associated social stigma have created substantial challenges for HIV prevention in this group. Despite these obstacles, several programmes have shown that HIV transmission in injecting drug users can be prevented, stabilised, and even reversed with needle exchange programmes.2 However, the HIV epidemic continues to grow in this high-risk population in some regions, particularly in eastern Europe, central Asia, and, since 2007, sub-Saharan Africa.3 Much more needs to be done to reduce the continuing high rates of HIV transmission in injecting drug users.

Findings from a series of randomised placebo-controlled trials, viewed cumulatively, provide compelling evidence (figure) that antiretroviral pre-exposure prophylaxis (PrEP), when taken, is effective in preventing mother-to-child transmission of HIV,4 sexual transmission in men who have sex with men, and sexual transmission between men and women.5 In women, both oral and topical antiretrovirals have been shown to prevent sexual transmission. However, there is no rigorous evidence on whether PrEP is effective in preventing parenteral HIV transmission. In 2005, the US Centers for Disease Control and Prevention initiated the Bangkok Tenofovir Study to address this major gap and assess the efficacy of daily oral tenofovir disoproxyl fumarate (tenofovir) in preventing parenteral transmission of HIV.

In The Lancet, Kachit Choopanya and colleagues report the results of this important study.6 They enrolled 2413 participants who reported injecting drugs within the previous 12 months and followed them up for a mean of 4·0 years. During follow-up, 50 participants acquired HIV: 17 were in the tenofovir group (HIV incidence=0·35 per 100 person-years) and 33 were in the placebo group (0·68 per 100 person-years), which translates into 49% effectiveness of tenofovir (95% CI 9·6—72·2). Additional per-protocol and drug level analyses drew attention to the importance of adherence to achieve high levels of protection from PrEP.

Although findings from this study provide the evidence to show that PrEP is effective in preventing HIV infection in people who inject drugs, it is less clear as to whether the findings show that PrEP prevents parenteral transmission of HIV. People who inject drugs can acquire HIV through either unprotected sexual intercourse or sharing of needles and syringes. These two routes of HIV transmission are often linked epidemiologically. Not only do injecting drug users engage in unprotected sex, they might also engage in commercial sex to get money for drugs.

Because no biological marker exists to distinguish between HIV transmission that occurs through sex and that which occurs parenterally, all HIV infections during follow-up in this trial contribute to the overall efficacy measure. Tenofovir is known to be effective in preventing sexual transmission of HIV, so some fraction of the recorded 49% protection is probably due to prevention of sexual transmission, in view of the fact that the number of reports of multiple sexual partners decreased during follow-up. The extent of the remaining protection attributable to parenteral transmission is not known. However, although the participants in this trial were confirmed injecting drug users at enrolment, there were substantial reductions in reported levels of injecting drug use from enrolment to month 12 (from 63% to 23%) and needle-sharing (from 18% to 2%). These reductions continued—by 72 months, 18% reported injecting drugs and 1% reported needle-sharing. Furthermore, the investigators noted that the protective benefits of PrEP were evident only after the first 3 years of follow-up, by which time reported levels of injecting drug use and needle-sharing were low. Hence, it is not possible to make definitive conclusions about the efficacy of daily tenofovir for the prevention of parenteral transmission of HIV from these data. As a result, PrEP is not a replacement for politically sensitive needle exchange programmes to prevent parenteral transmission.

Even though questions remain about the extent to which PrEP can be effective in preventing either of the routes of transmission in this group, the overall result is that daily tenofovir does reduce HIV transmission in injecting drug users. The introduction of PrEP for HIV prevention in injecting drug users should be considered as an additional component to accompany other proven prevention strategies like needle exchange programmes, methadone programmes, promotion of safer sex and injecting practices, condoms, and HIV counselling and testing. PrEP as part of combination prevention in injecting drug users could make a useful contribution to the quest for an AIDS-free generation.

Source: Lancet

 

Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial.

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Summary

Background

Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users.

Methods

In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20—60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered withClinicalTrials.gov, number NCT00119106.

Findings

Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0·35 per 100 person-years) and 33 in the placebo group (0·68 per 100 person-years), indicating a 48·9% reduction in HIV incidence (95% CI 9·6—72·2; p=0·01). The occurrence of serious adverse events was much the same between the two groups (p=0·35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0·002).

Interpretation

In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs.

Discussion

Once-daily oral tenofovir decreased the risk of HIV infection by 48·9% in injecting drug users when provided with other HIV prevention services at drug-treatment clinics in Bangkok. Findings from other pre-exposure prophylaxis trials showed that adherence had an important effect on efficacy.11, 12 In this study, efficacy increased from 46% to 56% in the per-protocol analysis based on observed adherence and to 74% when limited to participants with detectable tenofovir concentrations. Although the trial was not powered to assess efficacy in subgroups, we saw higher efficacy in women (79%) and in participants aged 40 years or older (89%)—two subgroups with high levels of adherence. The modified intention-to-treat efficacy result did not rule out tenofovir efficacy at less than 10% as specified in the protocol.

We do not know why HIV incidence in the two groups did not differ consistently until after 36 months (figure 2). Low levels of adherence or low risk behaviour during the first 36 months could have masked the effect of tenofovir, but adherence did not change by time on study and risk behaviour decreased during follow-up. The low HIV incidence and slow accrual of infections might be why no between-group difference was seen before 36 months. At 36 months, there were 27 infections and, assuming 49% efficacy, the distribution should have been nine with tenofovir and 18 with placebo. However, there were 13 with tenofovir and 14 with placebo, a difference of only four events.

As has been reported in other trials,11, 12 participants in the tenofovir group reported more nausea and vomiting in the first couple of months of follow-up than did those in the placebo group. When used for treatment of HIV, tenofovir is associated with small decreases in renal function.26, 27 We did not find higher rates of increased creatinine or renal disease in participants randomly allocated to tenofovir.

Other pre-exposure prophylaxis trials have described antiretroviral-resistance mutations in HIV-positive participants, especially in those with unrecognised HIV infection at enrolment.11—13 We did not detect tenofovir resistance in HIV-positive participants in this study. The two participants with unrecognised HIV infection at enrolment were randomly allocated to placebo, limiting the possibility that acquired resistance would occur.

Participant reports of injecting drugs and sharing needles decreased during follow-up, consistent with previous trials in people who inject drugs in Bangkok.28, 29 The HIV incidence in placebo recipients in our study was 0·68 per 100 person-years. This incidence compares with an incidence of 5·8 per 100 person-years in a preparatory trial done in the same clinics in 1995—99 and of 3·4 per 100 person-years during the 1999—2003 AIDSVAX B/E HIV vaccine trial.22, 28 This decrease over time is probably due to many factors, including monthly HIV risk-reduction counselling, decreased needle sharing, and monthly HIV testing speeding up the diagnosis of HIV and limiting the number of people with unrecognised acute HIV infection able to transmit HIV to others.

Our study had several limitations. Participants could have under-reported stigmatised and illegal behaviours such as injecting drugs.30 However, the illegality and stigma attached to these activities did not change during the trial, meaning that rates of under-reporting should have remained constant. The study aimed to establish whether tenofovir would reduce parenteral HIV transmission, but participants might have become infected sexually. Previous studies in people who inject drugs in the same clinics in Bangkok have shown strong associations between injecting drugs and HIV infection, but no association between sexual activity and HIV infection.28, 29 In this study, although reports of injecting drug use decreased, 1018 (45%) participants reported injecting drugs during follow-up, including 35 (70%) of those who contracted HIV during the course of the study. Furthermore, similar to the previous studies in the drug-treatment clinics, drug overdose, traffic accidents, and sepsis were the most common causes of death, and participants were frequently incarcerated. Together these data suggest that participants were actively injecting drugs and that parenteral HIV transmission, not sex, was the primary route of HIV infection. Additional risk behaviour analyses are underway. The study was done in drug-treatment clinics offering a package of HIV prevention interventions and DOT; tenofovir effectiveness might differ in other settings.

Findings from three randomised, placebo-controlled trials have shown that a daily dose of tenofovir or tenofovir-emtricitabine can reduce sexual HIV transmission.11—13 Findings from two other studies showed that tenofovir and tenofovir-emtricitabine did not reduce sexual HIV transmission.31, 32 Adherence seems to be the key factor determining efficacy.33These trials draw attention to the need for methods to help people using pre-exposure prophylaxis achieve effective levels of adherence.

To our knowledge, this study is the first to show that daily oral pre-exposure prophylaxis with tenofovir, when used in combination with other HIV prevention strategies, reduces the risk of HIV infection among people who inject drugs (panel). The US Food and Drug Administration has approved the use of tenofovir-emtricitabine to prevent sexual acquisition of HIV in high-risk individuals.34 On the basis of the results of this study, regulatory and public health authorities can now consider whether pre-exposure prophylaxis with tenofovir should be part of an HIV prevention package to reduce the risk of HIV infection in people who inject drugs.

Panel

Research in context

Systematic review

We searched PubMed for phase 1, 2, and 3 randomised clinical trials in human beings assessing tenofovir for the treatment of HIV infection and animal trials using tenofovir to prevent HIV infection. We used the search terms “HIV”, “tenofovir”, “treatment”, “prevention”, and “clinical trials”, restricting our search to studies published in English through December, 2004. The study was launched in 2005 and, at the time, no phase 3 clinical trials using tenofovir in human beings for HIV pre-exposure prophylaxis had published results.

Interpretation

To our knowledge, this is the first study to show that daily oral pre-exposure prophylaxis with tenofovir, when used in combination with other HIV prevention strategies, reduces the risk of HIV infection in people who inject drugs. Much like findings from other pre-exposure prophylaxis trials, our findings showed that adherence had an important effect on efficacy. On the basis of these findings regulatory and public health authorities can now consider whether pre-exposure prophylaxis with tenofovir should be part of an HIV prevention package to reduce the risk of HIV infection in people who inject drugs.

Source: http://www.thelancet.com

Renal Safety of Treatment for Chronic HBV Infection.

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Nephrotoxicity was similar with tenofovir or entecavir.

Both tenofovir and entecavir are considered first-line oral antiviral agents for chronic hepatitis B virus (HBV) infection. In previous studies, nephrotoxicity has been observed with tenofovir therapy in patients coinfected with HBV and HIV. However, whether similar renal toxicity is present during tenofovir therapy in patients with HBV monoinfection is unclear.

This community-based, retrospective study compared nephrotoxicity in 80 patients with HBV infection who were treated with tenofovir (300 mg with varying frequency) — alone or in combination with another antiviral — and in 80 age- and sex-matched patients treated with entecavir alone (0.5 mg or 1 mg with varying frequency). Nephrotoxicity was defined as an incidence of serum creatinine (SCr) 2.5 mg/dL, an increase in SCr of 0.2 mg/dL, a drop in the estimated glomerular filtration rate (eGFR) to <60 mL/min, or an adjustment in medication dosage. The tenofovir and entecavir groups were similar in proportions of patients with diabetes mellitus (20% in each group), history of kidney or liver transplant (20% and 16%), and preexisting renal insufficiency (19% and 13%).

During treatment (mean duration, 80 weeks with tenofovir and 111 weeks with entecavir), more patients in the tenofovir versus the entecavir group had an eGFR <60 mL/min (15 vs. 6; P=0.022) and required medication dose adjustment (13 vs. 4; P=0.021). However, more patients in the entecavir versus the tenofovir group developed a SCr 2.5 mg/dL (6 vs. 1; P=0.053). Of note, in multivariate analysis, therapy assignment was not associated with an increase in SCr of 0.2 mg/dL or in eGFR <60 mL/min. Only history of organ transplant and preexisting renal insufficiency were associated with an increase in SCr of 0.2 mg/dL.

Comment: Renal adverse events were similar in patients receiving either tenofovir or entecavir for treatment of HBV infection. These findings are similar to those of long-term safety studies for both agents based on the treatment cohorts in their phase III registration trials. Clinicians should keep in mind that other patient factors, such as preexisting renal insufficiency, also increase the risk for renal adverse events.

Source: Journal Watch Gastroenterology

 

What Is the Optimal First Line Antiretroviral Therapy in Resource-Limited Settings?

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Choosing an optimal first line antiretroviral therapy (ART) in resource-limited settings (RLS) involves a careful balancing act. On the one hand, we would want to ensure that patients receive the most efficacious therapy available. On the other hand, the most efficacious regimens may be too costly for countries afflicted by the dual burdens of very high HIV prevalence and of resource scarcity. This dilemma is compounded by the recent emergence of good quality evidence to start ART earlier (i.e., at higher CD4 counts), which can improve life expectancy [1], reduce the risk of tuberculosis acquisition [1], and reduce the transmission of HIV [2]. These considerations will mean that about 9 million extra people will need to be placed on ART by 2015 [3]—all in the context of a decline in global funding for AIDS during 2009 and 2010 [3].

The World Health Organization (WHO) has thus advised that countries should consider a number of factors in addition to clinical efficacy when considering choice of ART. These include in-country ART costs, numbers of current and future individuals needing to start ART, and the country’s national prevalence of chronic hepatitis B, tuberculosis, and anemia [4].

PEARLS Contributions Top

In a new study published in this week’s PLoS Medicine, Thomas Campbell and colleagues compared the efficacy and safety of three ART regimens for treatment naïve patients in the Prospective Evaluation of Antiretroviral Therapy in Resource-Limited Settings (PEARLS) trial [5]. They conducted a randomized controlled trial to compare the efficacy and safety of open-label ART with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-DF (EFV+FTC-TDF). Of note, their study population was considerably more representative of the global population of people with HIV than many other studies. The study population of 1,571 individuals with HIV-1 was drawn from nine countries (including eight low- and middle-income countries) in four continents. Forty-seven percent were women.

The trial found that ATV+DDI+FTC was inferior to EFV+3TC-ZDV in terms of treatment efficacy (21% and 15% treatment failures, respectively). EFV+3TC-ZDV and EFV+FTC-TDF were equally efficacious (19% and 18% treatment failures, respectively). This is in contrast to the only other randomized controlled trial to have evaluated the relative efficacy of these two regimens (GS-01-934), which found EFV+FTC-TDF to be more efficacious than EFV+3TC-ZDV [6]. In common with other trials, PEARLS found that the EFV+ZDV-3TC regimen was associated with more side effects requiring drug substitution than the EFV+FTC-TDF regimen.

How do we explain the discrepant findings between PEARLS and GS-01-934? The authors of PEARLS provide a plausible explanation relating to differences in how the primary efficacy endpoints were defined. GS-01-934 used as primary endpoint the US Food and Drug Administration (FDA) time to loss of virologic response (TLOVR). This includes all antiretroviral (ARV) substitutions as endpoints (failures). The ZDV containing arm had more adverse events than the TDF arm (22 versus 9), and this was the main determinant of the difference in primary endpoint between the two arms. Their explanation is given further credence by a reanalysis of PEARLS using the FDA-recommended TLOVR as the primary outcome. This transformed the PEARLS outcomes to concur with those of GS-01-934—the TDF regimen was superior.

In our opinion, a cogent case can be made that including protocol-pre-specified drug substitutions in an efficacy endpoint that is labeled as virological suppression is misleading. Both the rates of virological suppression and drug side effects are important endpoints, but it is unhelpful and misleading to conflate the two into one category and then label this as virological suppression. Of further note, the analytical approach taken in GS-01-934 favoured the commercial funder of the trial, Gilead Sciences. Six of the 12 authors of GS-01-934 were employees of Gilead, who manufacture TDF, and according to the authors of GS-01-934, “the study was designed by and the data were analyzed at Gilead Sciences” [6].

Practical Implications Top

The PEARLS study provides further evidence to back up the first two of four ART regimens listed by the WHO guidelines as acceptable first line ART regimens: AZT +3TC+EFV, TDF+3TC (or FTC)+EFV, AZT+3TC+NVP, and TDF+3TC (or FTC)+NVP [4].

PEARLS confirms the widely held view that TDF/FTC/EFV is an excellent first line ART regimen for use in RLS [7]. Its advantages include daily dosing, availability in a fixed dose combination, compatibility with tuberculosis treatment, effect on hepatitis B, low rates of side effects, and more recently the fact that the cheapest generic price for TDF is lower than that of the equivalent for ZDV [3]. The ability of RLS to access the cheapest ARVs varies dramatically [3],[8]. The evidence from PEARLS that ZDV has equivalent virological suppression to TDF could be used by these countries and others to further link ZDV and TDF in competitive price reductions.

One of the most useful contributions that PEARLS makes to our knowledge of ART is the lack of heterogeneity of efficacy or toxicity of ART according to country, continent, race, and/or ethnicity. There have been numerous concerns raised in the literature that there may be increased risks of drug toxicity from particular ARVs in specific populations. It has been argued that there is a risk that both TDF [9] and EFV [10] would have greater side effect rates in African populations. Reassuringly, PEARLS found no evidence of differential efficacy or toxicity by country, continent, race, or ethnicity.

Future Studies Top

Nevertheless, there are a number of limitations with the PEARLS trial that point the way for future research. One of these is the choice of protease inhibitor (PI)-based ART—unboosted ATV/DDI/FTC. A number of trials have shown the superiority of boosted- over unboosted-ATV, and this is now widely regarded as best practice [11]. A further problem is the inclusion of DDI, a drug whose toxicity and complexity in dosing has led to its exclusion from numerous guidelines for first line ART. It was thus not surprising that this regimen was less efficacious than EFV+3TC/ZDV. Given the suboptimal nature of this regimen, one certainly cannot generalize the findings to other PI-based ART. PI-based ART may be a good option for first line ART in RLS in persons who have been exposed to ARVs in the form of the prevention of mother-to-child transmission or pre-exposure prophylaxis [12]. Other first line regimens in need of further research in RLS are regimens including nevirapine 400 mg daily and rilpivirine (which has less neuropsychiatric side effects than EFV, and could possibly be produced for as little as US$10 per patient per year but is somewhat less effective in patients with high baseline viral loads [3]). New ARVs that may become options for the future include an alternative pro-drug version of tenofovir, GS-7340, which requires a lower dose and could be considerably cheaper than TDF [13]. PEARLS has provided policy makers and clinicians in RLS with reassurance of the equivalence, as far as virological suppression is concerned, of EFV+3TC-ZDV and EFV+FTC-TDF. For the reasons mentioned above, TDF containing ART will remain the optimal first line ART in RLS. Unfortunately, we remain a long way from ensuring that all ART-requiring patients in RLS receive optimal ART rather than more toxic regimens, or no ART at all.

Author Contributions Top

Conceived and designed the experiments: Wrote the first draft of the manuscript: CRK. Contributed to the writing of the manuscript: RC. ICMJE criteria for authorship read and met: CRK RC. Agree with manuscript results and conclusions: CRK RC.

References Top

  1. Severe P, Juste MA, Ambroise A, Eliacin L, Marchand C, et al. (2010) Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 363: 257–265. Find this article online
  2. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, et al. (2011) Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 365: 493–505. Find this article online
  3. Medecins Sans Frontieres (n.d.) Access to antiretrovirals; Untangling the Web of ARV Price Reductions. Available: http://utw.msfaccess.org. Accessed 30 May 2012.
  4. WHO (2010) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach – 2010 revision. World Health Organization Find this article online
  5. Campbell TB, Smeaton LM, Kumarasamy N, Flanigan T, Klingman KL, et al. (2012) Efficacy and safety of three antiretroviral regimens for initial treatment of hiv-1: a randomized clinical trial in diverse multinational settings. PLoS Med 9: e1001290 10.1371/journal.pmed.1001290.
  6. Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, et al. (2006) Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354: 251–60. Find this article online
  7. Jouquet G, Bygrave H, Kranzer K, Ford N, Gadot L, et al. (2011) Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource-limited setting in rural Lesotho. J Acquir Immune Defic Syndr 58: e68–e74. Find this article online
  8. Wirtz VJ, Santa-Ana-Tellez Y, Trout CH, Kaplan WA (2012) Allocating scarce financial resources for HIV treatment: benchmarking prices of antiretroviral medicines in Latin America. Health Policy Plan. Epub ahead of print 24 February 2012 Find this article online
  9. Kenyon C, Wearne N, Burton R, Meintjes G (2011) The risks of concurrent treatment with tenofovir and aminoglycosides in patients with HIV-associated Tuberculosis. South Afr J HIV Med 43–45. Find this article online
  10. Cohen K, Grant A, Dandara C, McIlleron H, Pemba L, et al. (2009) Effect of rifampicin-based antitubercular therapy and the cytochrome P450 2B6 516G>T polymorphism on efavirenz concentrations in adults in South Africa. Antivir Ther 14: 687–695. Find this article online
  11. Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, et al. (2010) Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 304: 321. Find this article online
  12. Kambugu A (2012) Pre-ART HIV resistance testing in Africa: are we there yet? Lancet Infect Dis 12: 261. Find this article online
  13. Markowitz M, Zolopa A, Ruane P (2011) GS-7340 demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston.

Source: PLOS

 

 

 

CDC Issues Guidance on Pre-Exposure Prophylaxis for HIV in Heterosexual Adults.

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The CDC has released interim recommendations on providing pre-exposure prophylaxis (PrEP) to prevent HIV in very-high-risk heterosexual adults — for example, those whose partners are infected.

Among the recommendations, published in MMWR:

  • Before prescribing PrEP, clinicians should screen patients for sexually transmitted infections and hepatitis B.
  • Clinicians should explain to women that the effect of the drugs on the developing fetus is not fully known, but no harms have been reported so far. Breast-feeding mothers should not receive PrEP.
  • When pregnant women take PrEP, clinicians can anonymously submit data on the pregnancy to the Antiretroviral Pregnancy Registry.
  • Tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine (FTC) 200 mg (i.e., one Truvada tablet) should be taken daily, and patients should be given no more than a 90-day supply.
  • HIV tests should be administered every 2 to 3 months.
  • Women should take a pregnancy test at each follow-up visit.

Source: MMWR

 

Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals.

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More than 30 years into the global HIV/AIDS epidemic, infection rates remain alarmingly high, with over 2.7 million people becoming infected every year. There is a need for HIV prevention strategies that are more effective. Oral antiretroviral pre-exposure prophylaxis (PrEP) in high-risk individuals may be a reliable tool in preventing the transmission of HIV.

Objectives

To evaluate the effects of oral antiretroviral chemoprophylaxis in preventing HIV infection in HIV-uninfected high-risk individuals.

Search methods

We revised the search strategy from the previous version of the review and conducted an updated search of MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in April 2012. We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing trials.

Selection criteria

Randomised controlled trials that evaluated the effects of any antiretroviral agent or combination of antiretroviral agents in preventing HIV infection in high-risk individuals

Data collection and analysis

Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors using a standardized data extraction form. Relative risk with a 95% confidence interval (CI) was used as the measure of effect.

Main results

We identified 12 randomised controlled trials that meet the criteria for the review. Six were ongoing trials, four had been completed and two had been terminated early. Six studies with a total of 9849 participants provided data for this review. The trials evaluated the following: daily oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms: TDF, TDF-FTC and placebo arm. The studies were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, serodiscordant couples and other high risk men and women.

Overall results from the four trials that compared TDF-FTC versus placebo showed a reduction in the risk of acquiring HIV infection (RR 0.51; 95% CI 0.30 to 0.86; 8918 participants). Similarly, the overall results of the studies that compared TDF only versus placebo showed a significant reduction in the risk of acquiring HIV infection (RR 0.38; 95% CI 0.23 to 0.63, 4027 participants). There were no significant differences in the risk of adverse events across all the studies that reported on adverse events. Also, adherence and sexual behaviours were similar in both the intervention and control groups.

Authors’ conclusions

Finding from this review suggests that pre-exposure prophylaxis with TDF alone or TDF-FTC reduces the risk of acquiring HIV in high-risk individuals including people in serodiscordant relationships, men who have sex with men and other high risk men and women.

 

Plain language summary

Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals

This review evaluated the effects of giving people at high risk for HIV infection drugs to prevent infection (called antiretroviral pre-exposure prophylaxis, or PrEP). We found six randomised controlled trials that assessed the effects of oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo, and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms (TDF, TDF-FTC and placebo arm). The trials were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, people in serodiscordant sexual relationships where one partner is infected and the other is not, and other high risk men and women. The findings suggests that the use of TDF alone or TDF+FTC reduces the risk of becoming infected with HIV. However, further studies are need to evaluate the method of administration (daily versus intermittent dosing), long-term safety and cost effectiveness of PrEP in different risk groups and settings.

Source: Cochrane Library.

 

High-dose vitamin D improved bone health in HIV patients on tenofovir.

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Significant monthly doses of vitamin D decreased hormonal changes that lead to bone loss among HIV patients assigned tenofovir, according to an NIH press release.

“What we’ve found suggests vitamin D could be used to counteract one of the major concerns about using tenofovir to treat HIV,” said Rohan Hazra, MD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. “People in their teens and 20s may be on anti-HIV treatment for decades to come, so finding a safe and inexpensive way to protect their long-term bone health would be a major advance.”

The study included 200 participants aged 18 to 25 years assigned tenofovir or other forms of anti-HIV treatment. Participants were administered a monthly 50,000-unit dose of vitamin D or placebo. The recommended daily dose of vitamin D is 600 units.

At the end of 3 months, researchers observed a 14% decrease in parathyroid hormone levels among participants assigned tenofovir, whereas no decrease was observed among those assigned other types of anti-HIV therapies.

No adverse effects from vitamin D were observed.

A follow-up study will be conducted to examine the long-term safety of vitamin D in a similar group of HIV-infected youth assigned antiretroviral regimens containing tenofovir and to determine whether the changes in parathyroid hormone result in improvements in bone density, according to the press release.

Source:Endocrine Today.

SATURN and AIM-HIGH: ‘Back down to planet Earth’

Again this year, clinical trials evaluating lipoprotein-modifying therapies were in the spotlight at the American Heart Association Scientific Sessions 2011, with concurrent publications in The New England Journal of Medicine.

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) is a prospective, randomized, multicenter, double blind clinical trial led by Stephen J. Nicholls, MD, Steven E. Nissen, MD, and colleagues. These investigators performed serial intravascular ultrasound (IVUS) at baseline and after 104 weeks of treatment in 1,039 patients with coronary heart disease.

Patients were randomly assigned to treatment with atorvastatin (Lipitor, Pfizer) 80 mg daily or rosuvastatin (Crestor, AstraZeneca) 40 mg daily. The rosuvastatin group attained lower LDL levels than the atorvastatin group (63 mg/dL vs. 70 mg/dL; P<.001) and slightly higher levels of HDL (50 mg/dL vs. 49 mg/dL; P=.01); however, the primary efficacy endpoint — percent atheroma volume — did not differ between the groups. Coronary atherosclerosis regressed with both treatment strategies: by 0.99% (95% CI, –1.19 to –0.63) with atorvastatin and by 1.2% (95% CI, –1.52 to –0.90) with rosuvastatin. Both agents induced regression in most patients: 63% with atorvastatin and 68.5% with rosuvastatin.

AIM-HIGH

In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial, 3,414 patients with established cardiovascular disease were randomly assigned to extended-release niacin 1,500 mg to 2,000 mg daily or matching placebo with 50 mg of niacin per tablet to mask treatment identity. Both groups received simvastatin (Zocor, Merck) 40 mg to 80 mg and ezetimibe (Vytorin, Merck/Schering-Plough) 10 mg daily, as needed, to maintain LDL levels between 40 mg/dL and 80 mg/dL.

The trial was stopped for a lack of efficacy after an average follow-up of 3 years. Despite an improvement in the lipid profile, including a significant increase in median HDL from 35 mg/dL to 42 mg/dL, there was no difference between the groups in the incidence of the primary composite endpoint of CHD death, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome (ACS) or symptom-driven coronary or cerebral revascularization.

It was clearly a challenge to end the AIM-HIGH trial after a mean follow-up of 3 years. The rise in strokes may have been a chance finding because many of the participants assigned niacin who sustained a stroke had stopped their niacin a number of months before. The Coronary Drug Project did not find an excess rate of stroke with niacin but did report an excess incidence of atrial fibrillation, a major risk factor for stroke. The rate of AF was not reported in the AIM-HIGH participants by treatment group. The other point to consider is that the event curves in the Cholesterol and Recurrent Events (CURE) study did not separate until after 2 years; this trial compared pravastatin (Pravachol, Teva Pharmaceuticals) vs. placebo. The 3-year follow-up may not have been long enough in AIM-HIGH because the trial mandated equal LDL levels that were accomplished by a greater use of ezetimibe in those not receiving niacin. Only HDL and triglyceride levels differed between treatment groups.

Trials viewed in tandem

SATURN and AIM-HIGH address opposite sides of the coin in some respects — SATURN aimed low with potent statin therapy, whereas AIM-HIGH did (as its name implies) with add-on niacin. The primary endpoint of SATURN was imaging-based and the primary endpoint of AIM-HIGH was clinical outcomes. However, at the core, both trials assessed two competing lipoprotein management strategies for patients with atherosclerotic vascular disease, with modest differential results on patients’ lipid profiles, and found neutral effects on the primary endpoints.

Some may be surprised, and others may not. Either way, as both camps reconvene back down on planet Earth, two key questions are:

  • How do we reconcile these studies with existing literature?
  • What is the bottom line when it comes to managing our patients?

Reconciling data with existing literature

Reconciling these studies may have a lot to do with endpoints. Painting with broad strokes, there is a ladder of endpoints, starting with hard clinical points, running down to soft clinical endpoints, to imaging endpoints, on down to biomarker endpoints. Ultimately, we want to be confident that if we see a change in an endpoint in response to a therapy, then this means we are benefiting patients. As it turns out, this is easier said than done. SATURN and AIM-HIGH raise important questions about surrogate imaging endpoints because SATURN employs one and AIM-HIGH was immediately preceded by a positive trial based on one: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER-6-HALTS).

Regarding SATURN, as pioneered by Drs. Nicholls and Nissen, and accepted by the expert community, IVUS quantifies plaque burden by percent atheroma volume, subtracting lumen area from the total area within the external elastic membrane divided by the total area. If different calculations are used, as in the secondary endpoint of SATURN, then a signal is seen for rosuvastatin trumping atorvastatin in atherosclerosis regression, but the clinical significance is unclear. Also unclear is the fact that the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial failed to show plaque regression with high-dose atorvastatin, whereas SATURN showed such an effect.

Moreover, from the perspective of the individual patient, we are left with the question: Why do some patients regress on potent statin therapy, whereas others only stabilize and others even progress? Also, how much does atherosclerosis regression actually have to do with increases in HDL (15% in ASTEROID and 4% in SATURN)? This was highlighted as a possible mechanism in the publication of the A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) trial, but why was the same magnitude of HDL increase not seen in SATURN?

The limitations of IVUS in assessment of atherosclerosis progression were discussed by Navin Kapur, MD, and Roger S. Blumenthal, MD, in an editorial on the ASTEROID trial in the Journal of the American Medical Association in April 2006. Indeed, we simply do not know how reliably an IVUS measurement or serial IVUS measurements track with clinical outcomes.

The same can be said for serial carotid intima-media thickness data. Although ARBITER-6-HALTS showed a 0.014-mm improvement in carotid intima-media thickness with niacin, this did not translate into a clinical outcomes benefit during a 3-year period in AIM-HIGH. This is a disappointing result, but there were a number of reasons for tempered enthusiasm after ARBITER-6-HALTS, including its premature termination and the small number of patients studied, as laid out in an editorial by Erin Michos, MD, and Blumenthal accompanying publication of the original manuscript in NEJM. The discordance between ARBITER-6-HALTS and AIM-HIGH implies that we should not be relying on serial carotid intima-media thickness testing to determine the best therapies.

Rather, we should rely on clinical outcomes data. Although AIM-HIGH did not show benefit, this does not mean that the HDL hypothesis is dead. Indeed, several clinical trials of novel agents that raise HDL are undergoing investigation. AIM-HIGH also does not mean that niacin itself should dig an early grave.

It remains to be seen whether a modest incremental benefit can be detected in the much larger ongoing niacin trial, Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2-THRIVE), with results expected in 2013. Although a clinical outcomes trial, it is notable that AIM-HIGH patients were not the highest risk, and events were less than expected, so the original primary composite endpoint was amended to include hospitalization for an ACS (softened from “high-risk ACS”) or symptom-driven coronary or cerebral revascularization, which ended up accounting for most of the primary endpoints in the trial.

In some respects, the inclusiveness of the composite endpoint is a good thing because doctors, patients and payers care about hospitalizations and revascularizations; however, in other respects, it is a bad thing because it is a “softer” or less reliable endpoint because more subjectivity enters the equation.

It is not unrealistic to think that HPS-2-THRIVE could show a benefit. Even if it does, we must point out that it does not necessarily follow that the benefit is from HDL raising. Although niacin is associated with increased HDL concentrations, this does not tell us about reverse cholesterol transport and HDL functionality.

Niacin also lowers LDL or, perhaps more importantly, atherogenic lipoprotein particles. Through the particle lens, a clinical effect of niacin may be more clearly understood because the impact on atherogenic particles is modest, so a very large trial may be needed to detect an effect, especially in patients who are already aggressively treated.

The bottom line

At the end of the day, in our humble opinion, the message boils down to the same message that was loud and clear before these studies: In managing high-risk patients with atherosclerotic vascular disease, the primary emphasis should be on atherogenic lipoprotein-lowering through appropriately potent statin therapy. We predict that atorvastatin will continue to be the dominant statin given physicians’ and patients’ comfort with it, its compatibility with calcium channel blockers and because it approaches rosuvastatin in potency. Cost is a huge issue for patients and the health care system, especially today, and is tied to adherence, so the transition of atorvastatin to generic form will be another factor that makes this medication the dominant one in the statin market for many years to come.

As for niacin, for the time being, although it did not show a benefit as an add-on therapy in patients with low LDL in AIM-HIGH, it is still a reasonable agent for lipoprotein-lowering in patients who cannot tolerate a statin and as an add-on agent for patients above treatment targets despite maximally tolerated statin therapy.

Source:Endocrine Today.