Status-post residency, I decided to subscribe to The New England Journal of Medicine in an attempt to look awesome and scholarly in front of my neighbors. Since I began receiving the journal at the beginning of July, the weekly issues have remained stacked on top of my "hope chest", aka ottoman next to the sofa, accumulating dust for the most part and serving as the occasional coffee rest.
Volume 367 Number 5 happened to attract my attention today; it focused on articles pertaining to pre-exposure prophylaxis for HIV. To give some background, POST exposure prophylaxis (for HIV) has been around for a long time. If a person is exposed to HIV or at high risk of having been exposed, ie unprotected sex, rape, needle stick, the same medications used to treat HIV infection, antiretrovirals, can be used to reduce the risk of transmission or seroconversion to an active infection in the exposed person. Post-exposure prophylaxis is well established in medicine, but recently there has been an increase in studies looking at use of antiretrovirals, ARVs, BEFORE a person engages in an activity that increases risk of HIV infection; I'm talking about sex.
The iPrEX study opened the flood gates; it found reduced risk of HIV infection when men-who-have-sex-with-men, or MSM, took tenofovir-emtricitabine before engaging in high risk behavior. The aptly named "disco-dosing" was done hand in hand with education on transmission and condom use. The CAPRISA study released shortly after found a 39% reduction in HIV transmission when women in South Africa used a tenofovir vaginal gel before sexual intercourse. The medicated vaginal gel allowed women to take their health into their own hands especially in a culture that gave women little right to demand that their partners or husband wear a condom. Strangely, tenofovir vaginal gel failed to show any benefit in the VOICE study.
Three studies were published together in the August 2nd issue of NEJM comparing Truvada (emtricitabine-tenofovir) and placebo used daily for pre-exposure prophylaxis in heterosexual persons in Africa. The Partners PrEP study compared the use of emtricitabine-tenofovir or tenofovir alone to placebo in serodiscordant couples in East Africa, where one partner had a positive HIV status while the other was negative, and followed patients for a year. Relative to placebo, daily tenofovir decreased the risk of HIV transmission by 67% while daily use of emtricitabine-tenofovir reduced risk 75%. Patients taking emtricitabine-tenofovir had an increased risk of neutropenia, GI upset, and fatigue but no difference was seen in death or worsening kidney function (tenofovir can cause kidney toxicity). I was surprised that the majority of seronegative patients at baseline were men (62%).
The FEM-PrEP study evaluated the use of daily Truvada in HIV-negative, higher-risk women in Kenya, Tanzania, and South Africa. High risk was defined as woman whom had had at least one vaginal sex act in the past two weeks or more than one sex partner in the past month. All women were given access to condoms and other medications for contraception. While the study was stopped early due to futility, the investigators saw high pregnancy rates in both groups, including in women who were "taking" oral contraceptives. In addition, adherence rates were self reported as "high" and pill counts showed study drug adherence of 88%, while random drug-level testing showed less than 1/3 of patients were actually taking the study medication. Failure to show benefit may have been secondary to low adherence rates.
The TDF2 study, also published in the August 2, 2012 edition of The New England Journal of Medicine, compared the use of daily Truvada to placebo in sexually active, heterosexual adults in Botswana, which has the second highest HIV prevalence in the world. All patients were given condoms and counseling on HIV in addition to other HIV prevention services and all women enrolled also had to agree to use effective contraception during the course of the study. There was a 62.2% risk reduction for patients taking Truvada. It is interesting to note that while the FEM-PrEP study only enrolled "high risk" sexually active females, this study had no inclusion criteria for behavioral risk but did show a significant risk reduction of HIV infection.
Breakdown:
These studies will be instrumental in developing guidelines on populations where pre-exposure prophylaxis, or "disco-dosing" will be most beneficial in preventing infection. While the iPrEX and CAPRISA studies showed benefit to chemoprophylaxis of HIV, many questions remain. In my opinion, starting a daily antiretroviral in an otherwise healthy person puts them at risks of drug toxicities and is an additional burden on the health-care budget. The TDF2 study showed that heterosexual sexually active adults in Botswana could significantly reduce their risk of HIV with daily Truvada, yet it does not seem economically feasible to place all adults aged 18-39 in Botswana on the drug and furthermore encourages the formation of resistant strains to what is the first line NRTI combination for the treatment of HIV.
While these studies are beneficial in establishing cohorts that may benefit most from chemoprophylaxis, the results are conflicting, as seen in comparing the TDF2 study to the FEM-PrEP study and the CAPRISA study to the VOICE study. In addition to balancing risk of drug-induced toxicity to risk of contracting HIV, no studies as of yet have established the length of time a person needs to stay on PrEP. While emtricitabine and tenofovir are two of the better tolerated ARVs, all studies showed increased nausea, vomiting, dizziness, and drowsiness in patients taking the study medications. It may be difficult to convince otherwise healthy adults to add an additional medication to their daily routine that may come with a side effect burden.
To conclude, pre-exposure prophylaxis is undoubtably an exciting advance in HIV world, but despite growing numbers of studies, I just haven't been able to buy in quite yet.
References:
Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM 2010; 363(27):2787-99. (iPrEX)
Baeten JM et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. NEJM 2012; 367(5):399-410. (Partners PrEP)
Van Damme L et al. Preexposure prophylaxis for HIV infection among African women. NEJM 2012; 367(5):411-22. (FEM-PrEP)
Thigpen MC et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. NEJM 2012; 367(5):423-34. (TDF2)
Cohen MS, Baden LR. Preexposure prophylaxis for HIV- where do we go from here? NEJM 2012; 367(5):459-61.
Volume 367 Number 5 happened to attract my attention today; it focused on articles pertaining to pre-exposure prophylaxis for HIV. To give some background, POST exposure prophylaxis (for HIV) has been around for a long time. If a person is exposed to HIV or at high risk of having been exposed, ie unprotected sex, rape, needle stick, the same medications used to treat HIV infection, antiretrovirals, can be used to reduce the risk of transmission or seroconversion to an active infection in the exposed person. Post-exposure prophylaxis is well established in medicine, but recently there has been an increase in studies looking at use of antiretrovirals, ARVs, BEFORE a person engages in an activity that increases risk of HIV infection; I'm talking about sex.
Three studies were published together in the August 2nd issue of NEJM comparing Truvada (emtricitabine-tenofovir) and placebo used daily for pre-exposure prophylaxis in heterosexual persons in Africa. The Partners PrEP study compared the use of emtricitabine-tenofovir or tenofovir alone to placebo in serodiscordant couples in East Africa, where one partner had a positive HIV status while the other was negative, and followed patients for a year. Relative to placebo, daily tenofovir decreased the risk of HIV transmission by 67% while daily use of emtricitabine-tenofovir reduced risk 75%. Patients taking emtricitabine-tenofovir had an increased risk of neutropenia, GI upset, and fatigue but no difference was seen in death or worsening kidney function (tenofovir can cause kidney toxicity). I was surprised that the majority of seronegative patients at baseline were men (62%).
The TDF2 study, also published in the August 2, 2012 edition of The New England Journal of Medicine, compared the use of daily Truvada to placebo in sexually active, heterosexual adults in Botswana, which has the second highest HIV prevalence in the world. All patients were given condoms and counseling on HIV in addition to other HIV prevention services and all women enrolled also had to agree to use effective contraception during the course of the study. There was a 62.2% risk reduction for patients taking Truvada. It is interesting to note that while the FEM-PrEP study only enrolled "high risk" sexually active females, this study had no inclusion criteria for behavioral risk but did show a significant risk reduction of HIV infection.
Breakdown:
These studies will be instrumental in developing guidelines on populations where pre-exposure prophylaxis, or "disco-dosing" will be most beneficial in preventing infection. While the iPrEX and CAPRISA studies showed benefit to chemoprophylaxis of HIV, many questions remain. In my opinion, starting a daily antiretroviral in an otherwise healthy person puts them at risks of drug toxicities and is an additional burden on the health-care budget. The TDF2 study showed that heterosexual sexually active adults in Botswana could significantly reduce their risk of HIV with daily Truvada, yet it does not seem economically feasible to place all adults aged 18-39 in Botswana on the drug and furthermore encourages the formation of resistant strains to what is the first line NRTI combination for the treatment of HIV.
While these studies are beneficial in establishing cohorts that may benefit most from chemoprophylaxis, the results are conflicting, as seen in comparing the TDF2 study to the FEM-PrEP study and the CAPRISA study to the VOICE study. In addition to balancing risk of drug-induced toxicity to risk of contracting HIV, no studies as of yet have established the length of time a person needs to stay on PrEP. While emtricitabine and tenofovir are two of the better tolerated ARVs, all studies showed increased nausea, vomiting, dizziness, and drowsiness in patients taking the study medications. It may be difficult to convince otherwise healthy adults to add an additional medication to their daily routine that may come with a side effect burden.
To conclude, pre-exposure prophylaxis is undoubtably an exciting advance in HIV world, but despite growing numbers of studies, I just haven't been able to buy in quite yet.
Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM 2010; 363(27):2787-99. (iPrEX)
Baeten JM et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. NEJM 2012; 367(5):399-410. (Partners PrEP)
Van Damme L et al. Preexposure prophylaxis for HIV infection among African women. NEJM 2012; 367(5):411-22. (FEM-PrEP)
Thigpen MC et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. NEJM 2012; 367(5):423-34. (TDF2)
Cohen MS, Baden LR. Preexposure prophylaxis for HIV- where do we go from here? NEJM 2012; 367(5):459-61.
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