Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial

doi:10.1016/S0140-6736(09)62038-9

The Lancet

Volume 375, Issue 9717, 6–12 March 2010, Pages 824-833

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https://doi.org/10.1016/S0140-6736(09)62038-9 Get rights and content

Summary

Background

Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of aciclovir on HIV-1 progression.

Methods

In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to aciclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per μL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per μL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per μL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.

Findings

At enrolment, the median CD4 cell count was 462 cells per μL and median HIV-1 plasma RNA was 4·1 log₁₀ copies per μL. Aciclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned aciclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0·84, 95% CI 0·71–0·98, p=0·03). In those with CD4 counts ≥350 cells per μL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per μL by 19% (0·81, 0·71–0·93, p=0·002)

Interpretation

The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.

Funding

Bill & Melinda Gates Foundation.

Introduction

Recent expansion of access to antiretroviral therapy has had a large effect on disease progression and mortality of people with HIV-1 infection in resource-poor countries. However, only a third of people with HIV-1 who meet international antiretroviral therapy initiation guidelines are given these drugs.¹ The number of people needing antiretroviral therapy will continue to grow, despite constraints on antiretroviral programmes and resources—especially if increased CD4 thresholds are adopted for initiation of antiretroviral therapy (eg, 350 cells per μL). Moreover, most people infected with HIV-1 worldwide have counts that are higher than the therapy starting thresholds of 200 or 350 CD4 cells per μL. Thus, low-cost interventions to slow HIV-1 disease progression are needed for those who do not meet present anti-retroviral initiation guidelines.

Infection with herpes simplex virus type 2 is the most common cause of genital ulcer disease worldwide. Seroprevalence of this virus in people with HIV-1 ranges from 70% to more than 90%.² Reactivation of this herpes virus is common and often asymptomatic in HIV-1-infected people, occurring on about a third of days.³ Plasma and genital HIV-1 concentrations increase during reactivation,4, 5, 6, 7, 8 suggesting that herpes reactivation enhances HIV-1 replication, possibly through binding of herpes simplex virus proteins to the HIV-1 long-terminal repeat, raising concentrations of pro-inflammatory cytokines, or through infiltration of HIV-1 target cells in the genital tract.9, 10, 11

In view of the strong relation between raised plasma HIV-1 concentrations and increased speed of HIV-1 disease progression,12, 13 suppression of herpes virus type 2 has been regarded as a potential strategy to reduce HIV-1 concentrations and slow its progression. Researchers of five randomised trials14, 15, 16, 17, 18 of people dually infected with these viruses who were not taking antiretroviral therapy reported that daily herpes suppressive therapy with aciclovir or valaciclovir for 8–12 weeks reduced plasma HIV-1 concentrations by 0·25–0·5 log₁₀ copies per μL.14, 15, 16, 17, 18 We undertook a multicentre trial of daily suppression of herpes simplex virus type 2 with aciclovir in Africans who were dually infected with HIV-1 and herpes simplex virus type 2 to assess the efficacy of suppressive aciclovir on measures of HIV-1 disease progression.

Section snippets

Participants

Heterosexual couples who were discordant for HIV-1 infection were recruited at sites in southern Africa (Gaborone Botswana; Cape Town, Orange Farm, and Soweto South Africa; and Kitwe, Lusaka, and Ndola Zambia) and east Africa (Eldoret, Kisumu, Nairobi, and Thika, Kenya; Kigali Rwanda; Moshi Tanzania; and Kampala Uganda) between Nov 23, 2004 and May 16, 2007. Eligible HIV-1 infected partners were 18 years or older, seropositive for HIV-1 and herpes simplex virus type 2, and had a CD4 cell count

Results

Figure 1 shows the trial profile. Baseline demographic and clinical characteristics were similar between the two study groups (table 1). 68% of participants were women. The median baseline CD4 cell count was 462 cells per μL (IQR 347–631) and for HIV-1 plasma RNA was 4·1 log₁₀ copies per μL (3·4–4·7). Most participants had asymptomatic HIV-1 disease, with 5% or fewer reporting pneumonia, tuberculosis, or herpes zoster in the previous year. Retention of participants at 24 months of follow-up was

Discussion

Our results show that standard doses of aciclovir for suppression of herpes simplex virus type 2 in people infected with HIV-1 and herpes type 2 reduced the risk of HIV-1 disease progression by 16%. Fewer participants in the aciclovir group than in the placebo group had CD4 cell counts fall below 200 cells per μL (p=0·06), started antiretroviral therapy (p=0·05), or died from non-trauma-related reasons (p=0·29). Furthermore, fewer of those in the group assigned aciclovir with counts of 350

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2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
Antiviral medications are a necessary tool for dermatologists to manage common dermatologic problems, such as herpes simplex virus, varicella, and herpes zoster. Dermatologists must know the proper dosages and route of administration of valacyclovir, acyclovir, and famciclovir for management of these diseases. In addition, some preventative herpes virus vaccines have become available. A varicella zoster vaccine was approved in 1995, which has greatly reduced the number and severity of chickenpox cases. Zostavax, a live-attenuated vaccine, and Shingrix, a recombinant vaccine, were approved for the prevention of herpes zoster in 2006 and 2017, respectively. Because human immunodeficiency virus (HIV) infection often has dermatologic manifestations, it is helpful for dermatologists to be aware of the medications used to treat HIV. Furthermore, these medications also often have cutaneous adverse effects, which may prompt evaluation by a dermatologist. Combination medications containing drugs from one or more classes are becoming a mainstay of treatment. Managing HIV via multiple mechanisms of action is essential to decrease the risk of drug resistance and virologic failure. Preventative and therapeutic HIV vaccinations are continually being investigated, but no vaccines will be approved for use in the near future. To date, only one vaccination has demonstrated any efficacy in clinical trials.
Modeling HIV disease progression and transmission at population-level: The potential impact of modifying disease progression in HIV treatment programs
2018, Epidemics
Mathematical models that incorporate HIV disease progression dynamics can estimate the potential impact of strategies that delay HIV disease progression and reduce infectiousness for persons not on antiretroviral therapy (ART). Suppressive treatment of HIV-positive persons co-infected with herpes simplex virus-2 (HSV-2) with valacyclovir, an HSV-2 antiviral, can lower HIV viral load, but the impact of partially-suppressive valacyclovir relative to fully-suppressive ART on population HIV transmission has not been estimated.
We modeled HIV disease progression as a function of changes in viral load and CD4 count over time among ART naïve persons. The disease progression Markov model was nested within a dynamic model of HIV transmission at population level. We assumed that valacyclovir reduced HIV viral load by 1.23 log copies/μL, and that persons treated with valacyclovir initiated ART more rapidly when their CD4 fell below 500 due to retention in HIV care. We estimated the potential impact of valacyclovir on onward transmission of HIV in three scenarios of different ART and valacyclovir population coverage.
The average duration of HIV infection was 9.5 years. The duration of disease before reaching CD4 200 cells/μL was 2.53 years longer for females than males. Relative to a baseline of ART initiation at CD4 ≤ 500 cells/μL, the valacyclovir scenario resulted in 167,000 fewer HIV infections over ten years, with an incremental cost-effectiveness ratio (ICER) of $5276 per HIV infection averted. A Test and Treat scenario with 70% ART coverage and no valacyclovir resulted in 350,000 fewer HIV infections at an ICER of $2822 and $812 per HIV infection averted and QALY gained, respectively.
Even when compared with valacyclovir suppression, a drug that reduces HIV viral load, universal treatment for HIV is the optimal strategy for averting new infections and increasing public health benefit. Universal HIV treatment would most effectively and efficiently reduce the HIV burden.
Concordance of self-reported hormonal contraceptive use and presence of exogenous hormones in serum among African women
2018, Contraception
Studies that rely on self-report to investigate the relationship between hormonal contraceptive use and HIV acquisition and transmission, as well as other health outcomes, could have compromised results due to misreporting. We determined the frequency of misreported hormonal contraceptive use among African women with and at risk for HIV.
We tested 1102 archived serum samples from 664 African women who had participated in prospective HIV prevention studies. Using a novel high-performance liquid chromatography–mass spectrometry assay, we quantified exogenous hormones for injectables (medroxyprogesterone acetate or norethisterone), oral contraceptives (OC) (levonorgestrel or ethinyl estradiol) and implants (levonorgestrel or etonogestrel) and compared them to self-reported use.
Among women reporting hormonal contraceptive use, 258/358 (72%) of samples were fully concordant with self-report, as were 642/744 (86%) of samples from women reporting no hormonal contraceptive use. However, 42/253 (17%) of samples from women reporting injectable use, 41/66 (62%) of samples from self-reported OC users and 3/39 (8%) of samples from self-reported implant users had no quantifiable hormones. Among self-reported nonusers, 102/744 (14%) had ≥1 hormone present. Concordance between self-reported method and exogenous hormones did not differ by HIV status.
Among African women with and at risk for HIV, testing of exogenous hormones revealed agreement with self-reported contraceptive use for most women. However, unexpected exogenous hormones were identified among self-reported hormonal contraceptive users and nonusers, and an important fraction of women reporting hormonal contraceptive use had no hormones detected; absence of oral contraceptive hormones could be due, at least in part, to samples taken during the hormone-free interval. Misreporting of hormonal contraceptive use could lead to biased results in observational studies of the relationship between contraceptive use and health outcomes.
Research studies investigating associations between hormonal contraceptive use and HIV should consider validating self-reported use by objective measures; because both overreporting and underreporting of use occur, potential misclassification based on self-report could lead to biased results in directions that cannot be easily predicted.
Could misreporting of condom use explain the observed association between injectable hormonal contraceptives and HIV acquisition risk?
2017, Contraception
Some observational studies have suggested an association between the use of hormonal contraceptives (HC) and HIV acquisition. One major concern is that differential misreporting of sexual behavior between HC users and nonusers may generate artificially inflated risk estimates.
We developed an individual-based model that simulates the South African HIV serodiscordant couples analyzed for HC–HIV risk by Heffron et al. (2012). We varied the pattern of misreporting condom use between HC users and nonusers and reproduced the trial data under the assumption that HC use is not associated with HIV risk. The simulated data were analyzed using Cox proportional hazards models, adjusting for the reported level of condom use.
If HC users overreport condom use more than nonusers, an apparent excess risk could be observed even without any biological effect of HC on HIV acquisition. With 45% overreporting by HC users (i.e., 9 out of every 20 sex acts reported with condoms are actually unprotected) and accurate condom reporting by nonusers, a true null effect can be inflated to give an observed hazard ratio ( $\hat{HR}$ ) of 2.0. In a different population with lower overall reported condom use, artificially high $\hat{HR}$ s can only be generated if non-HC users underreport condom use.
Differential condom misreporting can theoretically produce inflated $\hat{HR}$ values for an association between HC and HIV even without a true association. However, to produce a doubling of HIV risk that is entirely spurious requires substantially different levels of misreporting among HC users and nonusers, which may be unrealistic.
Considerably differential amounts of condom use misreporting by HC users and nonusers would be needed to produce entirely spurious observed levels of excess HIV acquisition risk among HC users when there is actually no true association.

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ArticlesDaily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Participants

Results

Discussion

Virology

Lancet

Cell Host Microbe

J Biol Chem

Lancet

Lancet

Lancet

2008 Report on the global AIDS epidemic

Epidemiology of herpes simplex virus type 2 infection in the developing world

Herpes

Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy

J Infect Dis

Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial

J Infect Dis

Genital shedding of herpes simplex virus-2 DNA and HIV-1 RNA and proviral DNA in HIV-1- and herpes simplex virus-2-coinfected African women

J Acquir Immune Defic Syndr

The impact of active herpes simplex virus infection on human immunodeficiency virus load

J Infect Dis

Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men

JAMA

Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression

J Infect Dis

Herpes simplex virus type-1 can reactivate transcription of latent human immunodeficiency virus

Nature

Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract

AIDS

Higher set point plasma viral load and more-severe acute HIV type 1 (HIV-1) illness predict mortality among high-risk HIV-1-infected African women

Clin Infect Dis

Prognosis in HIV-1 infection predicted by the quantity of virus in plasma

Science

Herpes simplex virus (HSV)—suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial

J Infect Dis

Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa

AIDS

Suppressive acyclovir therapy reduces HIV cervicovaginal shedding in HIV- and HSV-2-infected women, Chiang Rai, Thailand

J Acquir Immune Defic Syndr

Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus

N Engl J Med

Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial

J Infect Dis

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2

N Engl J Med

Articles
Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial