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Achieving an end to the AIDS epidemic: Laying the groundwork


nAn abridged version of the lecture delivered at the Induction Ceremony of the Nigerian Academy of Sciences by Prof. John Idoko, FMCP, FAS. Idoko is also the Director-General, National Agency for the Control of AIDS (NACA).

COMMUNITY campaigns, including those that provide screening or prevention services for multiple diseases, have proven effective in Nigeria, Kenya, Malawi, South Africa, Uganda, the United Republic of Tanzania and Zambia. Further efforts are required to normalize HIV testing in health care settings. Recent efforts by Nigeria to provide HIV testing as the entry point for the minimum package of prevention interventions (MMPI) is encouraging and will rapidly increase the uptake of HIV counseling and testing. Pilot projects in both concentrated and generalized epidemic settings suggest that home-based testing is highly acceptable, in part because it protects confidentiality, as a complement to, rather than a replacement for, provider-initiated or facility-based HIV testing and counselling services.

Substantially increasing the demand for HIV testing is essential. This requires robust and sustained investment in community-based HIV literacy programmes. Enhanced support for strengthening community systems is also needed, to broaden awareness of the availability of simple, easily tolerated regimens, increase access to user-friendly testing options and alleviate stigmatizing attitudes that deter many from seeking testing services. Focused, community-centred testing outreach can help reach marginalized populations at elevated risk of HIV infection.

This new test adds p24 antigen to the HIV antibody test to permit detection of the disease before seroconversion. This new test can detect the presence of HIV in the first week of infection. Rapid tests, ELISA and Western blot (WB) detect positive samples only at seroconversion which occurs after 3 months of HIV infection. This test is approved by the US Food and Drug Administration (FDA), and its use is recommended by the Centers for Disease Control and Prevention (CDC) and will hopefully become available in low and middle income countries in the near future.

The test will be a very useful test for screening patients because it can detect HIV during the early acute retroviral syndrome stage unlike the WB results, which require waiting for 2-3 months after viral transmission. Advantages of this early detection include (1) the possibility of functional cure (discussed below); (2) treatment at the time of maximum risk for transmission; and (3) the opportunity for direct entry into HIV care vs. the long delay required for obtaining a positive WB result. This delay leads to 20%-25% of patients with a positive WB never actually receiving their results. Consequently, their care may be delayed or they may be lost to care.

Point-of-care (POC) HIV testing has been extremely successful as a screening tool to detect HIV. Now, there is a POC CD4 count test that permits staging HIV at the site of care and it is anticipated that a POC viral load test will also be available, although the timeline for this development is unclear. The advent of the POC CD4 and viral load tests permits patients to test their own viral load to facilitate HIV management in an outpatient setting, often without the need for frequent medical evaluation except to test for drug toxicity, Co-morbidities, and HIV-related complications. The long-term goal would be self-care akin to standard diabetes management.

Several studies have shown that when pregnant HIV positive women have access to antiretroviral drug combinations, the risk of transmitting the virus to their babies is less that 5%. As a result of this scientific information, access to Prevention of Mother to Child Transmission (PMTCT) of HIV services has increased dramatically. By 2012, 62% of pregnant women worldwide living with HIV had access to antiretroviral drug combinations and in several countries coverage levels are well above 80%.

However, Nigeria has made very slow progress (30% coverage) despite efforts at scaling up PMTCT due to a number of structural challenges including inadequate services at the level of PHC, poor attendance of pregnant women of antenatal care services; many women preferring to go to Traditional Birth Attendants (TBAs), churches and mosques to access antenatal care and delivery services. The core elements of the approach to accelerating PMTCT Scale up in Nigeria include; i) Intensive, state-focused approach to scale up, ii) Decentralization of services to primary care level, iii) Private sector engagement in PMTCT Service delivery, iv) focusing on the high burden MTCT states otherwise referred to as the 12+1 states (49) – these states are responsible for over 70% of the burden of HIV/AIDS in Nigeria.

Key stakeholders support the notion to better inform implementation efforts driven by a fact-base that is state-specific. This is hinged on the recent work in Nasarawa state where a diagnostic of the PMTCT landscape was conducted and where the outcome of the diagnostics is now being applied to shape program implementation and this has become the basis for regular state-level consultation to drive the program in other states. In the light of this, a new element has been introduced into the national approach to accelerate PMTCT scale up; this is State-specific diagnostics and profiling to inform implementation of scale-up activities and to enable state leaders to feel more ownership of and accountability for their results. This deep engagement with states and the diagnostics and potential revised plans that result will complement and be synergistic with ‘on-going’ PMTCT efforts in the 12+1 states including the work that is currently being supported by the Government of Nigeria and several partners.

There is now good evidence to show that the HIV reservoir in individuals with chronic HIV infection is substantial and is probably an important factor in immune activation. This explains our inability to achieve cure, despite viral suppression with traditional monitoring. “Cure” is now described in 2 categories: a “sterilizing cure,” in which the virus is eliminated, and a “functional cure,” in which the virus continues to be present but does not require antiretroviral therapy (ART) for viremic control. The “Berlin patient” who underwent stem cell transplantation is regarded as the only person to has achieved sterilizing cure. The “Mississippi baby” is considered a functional cure because she has had virologic control.

The “Mississippi baby” is considered a functional cure because she has had virologic control off therapy for longer than 1 year after being treated at birth and briefly after birth, but it is not clear that the virus is eliminated. Possibly the best example of the impact of early therapy is the VISCONTI cohort. This is a group of patients in France treated early in the course of HIV infection who have remained off ART for months or years, without treatment or detectable virus. The presumed explanation is that treatment early in the course of acute infection limits substantial infection of the reservoir. Thus, recognition of acute disease with rapid implementation of ART now becomes an important priority in the context of HIV management.

Researchers determined that initiation of antiretroviral therapy to an HIV-exposed infant 31 hours after birth succeeded in curing the infant of HIV. In early 2013, French researchers reported that 14 individuals were functionally cured after being treated with antiretrovirals during acute infection. In July 2013, two additional individuals were reported to be HIV-free after receiving bone marrow transplants, although experts cautioned that further follow-up was needed before drawing definitive conclusions. Although no broadly applicable cure for HIV is now available, these research results nevertheless increased optimism that a more widely available cure might someday be feasible.

Traditionally “Cure or sterilizing Cure” is talk about eradicating or eliminating disease. At this point in time it is not possible to routinely eliminate or eradicate HIV (except the Berlin patient as there are millions currently infected) but we can certainly bring down the HIV incidence to a level where the reproductive rate of infection is below 1. The world needs a countdown on the journey towards the End of AIDS in each country putting together a planned time table including:
•A nationally co-ordinated comprehensive response, including human rights and a legal framework that is conducive to non-discrimination against AIDS
•Detailed knowledge of the local epidemiology of HIV, including identifying hotspots, and application of that knowledge to guide investment and programming
•Scaling up provision of ART (as part of a comprehensive package of optimum care + medicines + adherence support) to 90% of those qualifying for treatment with 90% annual retention
•Elimination of mother-to-child transmission
•Number of patients initiating ART exceeds the number of new infections – Tipping Point
•The incidence rate (number of new infections in the population) reaches a low point where the reproductive rate of infection is less than 1. Each country will need to calculate and define this target level
•The number of new HIV infections reaches a point below the threshold established for each country (e.g. incidence rate where the reproductive rate of infection is 0.25)
•Once point 1 is reached, then at point 0, a new set of locally derived milestones are needed to get to zero new HIV infections along the path to the end of AIDS

The end of AIDS is an aspirational vision that we hope to achieve over the long term with a program for the next 10-15 years towards this vision. The end of AIDS encompasses reducing new HIV infections, providing ART to all who require treatment and reducing the stigma and discrimination that prevents people from accessing the care and treatment they need as well as maintaining them in care

Ending AIDS will require more than just biomedical solutions because AIDS is more than a biomedical problem. Ending Mother to Child Transmission (MTCT) in children is already achievable without a vaccine or cure. Ending HIV in everyone will require a cure but ending AIDS will not. We have existing interventions to address social drivers. We also have effective biomedical technologies, such as PMTCT, PrEP, Treatment as Prevention and male circumcision. Models show how we can set the global epidemic on the path to the end of the AIDS epidemic with current technologies noting that future new technologies are also needed to accelerate progress towards the end of AIDS.

After 30 years of the HIV-1 epidemic, novel and effective HIV-1 prevention strategies are urgently needed, particularly those that are deliverable to and useable by high-risk populations. To achieve impact at the population level with strategies that are proven efficacious in controlled trials, effective delivery systems and high uptake are critical. To lower the cost per averted infection, targeted delivery to those at highest risk for HIV-1 will be essential.
During the past 10 years, a growing scientific and advocacy interest in antiretroviral-based strategies for prevention of sexual HIV-1 transmission has developed, and antiretroviral-based HIV-1 prevention interventions are now among the most promising strategies for dramatically reducing the spread of HIV-1. Antiretroviral drugs have the potential to be used for HIV-1 prevention as 1) antiretroviral treatment (ART) to reduce the infectiousness of HIV-1 infected persons (TasP) and 2) oral or topical pre-exposure prophylaxis (PrEP) for uninfected persons with repeated and ongoing HIV-1 exposure.

ART reduces HIV-1 transmission by reducing HIV-1 plasma concentrations to undetectable levels within 6 months of initiation in the majority of persons and seminal and cervicovaginal HIV-1 concentrations are also reduced to undetectable levels in most persons on ART. Also, the use of peripartum ART is responsible for the remarkable success in virtually eliminating mother-to-child HIV-1 transmission in resource-rich settings. The efficacy of antiretrovirals for the prevention of mother-to-child transmission of HIV-1, first demonstrated with peripartum zidovudine was a proof of concept for the feasibility of preventing sexual acquisition of HIV-1 with PrEP. More recent studies have shown that post-natal administration of antiretroviral drugs, provided to infants who have ongoing exposure to HIV-1 through breast milk, can substantially reduce HIV-1 risk.

These infant studies provided compelling analogous evidence that antiretroviral prophylaxis could be highly efficacious for preventing infection in the context of known and ongoing HIV-1 exposure. Evidence from studies shows substantial reduction in HIV-1 quantity in the plasma and genital compartments of persons on suppressive ART, which translates into markedly reduced risk of HIV-1 transmission to sexual partners. This evidence has informed the need to explore the use of ART for HIV prevention in many settings including gay men (iprex study, and as microbicides for women.

A meta-analysis conducted by Attia et al. showed significantly lower risk of HIV-1 transmission in heterosexual discordant couples whose HIV positive partner was on ART. More recently, the Partners PrEP Study, a phase III, placebo-controlled trial of oral tenofovir disoproxyl fumarate (TDF) and combination emtricitabine (FTC)/TDF PrEP among HIV-1 uninfected partners in 4758 HIV-1 serodiscordant African couples, demonstrated that PrEP substantially reduced HIV-1 risk.

Across studies, adherence has been a key predictor of efficacy; very high adherence in the Partners PrEP Study likely explains the high degree of HIV-1 protection. Notably, two PrEP trials among African women – FEM-PrEP (using FTC/TDF) and VOICE (using TDF and tenofovir gel, with an FTC/TDF arm still ongoing) – failed to show HIV-1 protection. For one of these (FEM-PrEP), substantial lack of adherence (approximately only 25% consistent use of the study medication) likely explains the failure to show HIV-1 protection. Thus, while a number of factors could explain the divergent trial results, foremost is non-adherence. Importantly, for HIV-1 uninfected members of known HIV-1 serodiscordant couples, as shown in the Partners PrEP Study, adherence appears to be very high.

In a very recent follow-up report of the PARTNER study, all the heterosexual HIV-negative partners reported having vaginal sex without condoms, 72% with ejaculation; 70% of the gay HIV-negative partners reported having receptive anal sex without condoms, 40% with ejaculation, while 30% reported only being the insertive partner. A significant proportion of the heterosexual couples reported anal sex. The investigators estimated that the gay couples had sex on 16,400 occasions and the heterosexual couples on 14,000 occasions.

There were no cases of HIV transmission when viral load was below 200 copies/ml. Statistical analysis showed that an undetectable viral load reduced the risk of transmission during vaginal sex by 99.5% and during anal sex by 99% (96% with ejaculation). However, the researchers believe the true efficacy of treatment as prevention is likely to be nearer 100%, although, as the study’s principal investigator pointed out, it will probably never be possible to show with mathematical certainty that the risk of transmission from someone on successful HIV therapy is absolutely zero.

A clear and consistent message from stakeholders has been the need to prioritize access of ART and PrEP for high-risk populations. One such population is HIV-1 serodiscordant couples (i.e., one member is HIV-1 infected and the other uninfected). Population data from Africa suggest that a substantial fraction of new infections (up to half or more) may occur within stable serodiscordant marital or cohabiting relationships. Epidemiologic studies, national HIV-1 serosurveys, and mathematical modeling analyses indicate that stable, heterosexual HIV-1 serodiscordant couples account for a substantial proportion of new HIV-1 transmissions in East Africa.

Data from Nigeria also indicate that couples in stable relationships contribute significantly to HIV incidence. About 62% of new infections occur among persons perceived as practicing “low risk sex” in the general population, including married sexual partners. Evidence suggests that the magnitude of serodiscordance among pregnant couples is high and is a significant channel for transmitting new HIV infections. In Nigeria, about 7.7% to 78.7% of HIV positive pregnant women who access antenatal care have HIV negative male sex partners. The highest rates occurred among married couples in Southern Nigeria. Among the sero-discordant couples enrolled in the FHI 360 program, women were 11 times more likely to be the HIV positive partner than the HIV negative partner.

Understanding HIV-1 prevention choices and targeting prevention strategies to this group are public health priorities. In particular, HIV-1 serodiscordant couples have been specifically identified as a priority population for implementation of antiretrovial-based HIV-1 prevention, given their high risk, smaller number for targeting relative to the general population, ability to be targeted for prevention efforts through promotion of couples HIV-1 counseling and testing, and the clear advantage to the partnership in avoiding HIV-1 transmission. Importantly, both ART and PrEP have demonstrated high efficacy for HIV-1 protection when used by members of HIV-1 serodiscordant couples. WHO is poised to release guidelines for counseling and HIV-1 prevention for HIV-1 serodiscordant couples, which will include ART and PrEP as potential prevention strategy.

A large randomised study of treatment as prevention has closed more than three years early after interim analysis of the data showed that antiretroviral treatment reduced the risk of HIV transmission from treated partner to uninfected partner by 96%. The magnitude of the reduction in risk is almost the same as that observed in multiple cohort studies in sub-Saharan Africa, and is the strongest effect seen in any trial that has used an antiretroviral-based prevention method. HPTN 052 (67) is a large, international study which randomized 1736 male-female couples in which one partner was HIV-positive either to begin antiretroviral therapy immediately, or to wait until treatment was clinically indicated (at a CD4 count of 250 cells/mm3).

The study began enrolling participants in 2005 in Botswana, Brazil, India, Kenya, Malawi, South Africa and Zimbabwe, and recruited couples in which the HIV-positive partner had a CD4 cell count between 350 and 550 cells/mm3. The median CD4 count at the time of joining the study was 436 cells/mm3. This level is higher than the threshold at which World Health Organization guidelines currently recommend starting treatment. The study was due to run until 2015. The study was halted after an interim review by the Data and Safety Monitoring Board, which found that 39 infections had occurred. Twenty-eight could be genetically linked to the HIV-positive partner, and of these 27 occurred in couples where the HIV-positive partner did not begin antiretroviral therapy immediately.

This translates into a 96% reduction in the risk of transmission. This result was highly statistically significant (P<0.0001).

“This breakthrough is a serious game changer and will drive the prevention revolution forward. It makes HIV treatment a new priority prevention option,” said Michel Sidibé, Executive Director of the Joint United Nations Programme on HIV/AIDS (UNAIDS).

“Now we need to make sure that couples have the option to choose Treatment for Prevention and have access to it.” “People living with HIV can now, with dignity and confidence, take additional steps to protect their loved ones from HIV,” said Mr Sidibé. “The recent results from the iPrEx trial showed that PrEP is effective in gay men and transgender women, while the CAPRISA 004 microbicide trial showed that 1% tenofovir gel is effective at reducing HIV risk for women.”

“Together, these results allow us to imagine a world in which men and women seek HIV testing with the knowledge and confidence that they will receive a range of highly effective options for staying healthy and protecting themselves and their partners—whatever the test result,” Warren added. “The results of the study require us to rethink how we structure the delivery and funding of HIV services overall“.

Mathematical modeling by WHO has stimulated great interest in the potential of ART to substantially reduce population HIV-1 incidence when administered through near-universal annual HIV-1 testing, linkage to care, and uptake of ART, regardless of CD4 count (together called the ‘Test and Treat’ or ‘Test and Linkage to Care’ concept).

Most individuals are infected for several years before CD4 decline or clinical disease necessitates ART, and although WHO HIV-1 treatment guidelines now recommend ART initiation at CD4 counts

while ART adherence has been excellent in Africa, this success has been exclusively in individuals with advanced disease whose families are dedicated to provide tangible support to overcome severe structural and economic barriers to adherence because of the dramatic functional improvement they witness with ART. It is unclear whether asymptomatic individuals and their families will share the same commitment to adherence when ART is given to asymptomatic individuals.

HIV treatment combines drugs from different classes that interfere with different steps of the viral lifecycle but no existing drugs target the very first step – the initial attachment of the virus to a vulnerable host cell. The recent Conference of Retroviral and Opportunistic Infections held in Boston USA March 2014 heard that combination therapy using a novel HIV attachment inhibitor demonstrated good safety and effectiveness, offering the promise of a new antiretroviral class that may be particularly beneficial for people with extensive resistance to current drugs.

A multi-national trial evaluating the safety and efficacy of the attachment inhibitor currently known as BMS-663068 involved 253 treatment-experienced people. Participants had a mean CD4 cell count of around 230 cells/mm3 and many had experienced treatment failure with first- or second line HIV treatment. About half the participants had HIV with at least one major resistance mutation, but to be included in the study they had to have HIV that was still sensitive to raltegravir (Isentress), tenofovir (Viread, also in some co-formulations) and atazanavir (Reyataz). Participants were randomised to five groups, four groups taking different doses of the trial drug and one control group taking atazanavir boosted with ritonavir.

All groups also took raltegravir and tenofovir at week 24, all dosing groups had similar results: 80% of people taking 400mg twice daily, 69% taking 800mg twice daily, 77% taking 600mg once daily and 72% taking 1200mg twice daily had a viral load below 50 copies/ml, compared with 75% in the atazanavir control arm. BMS-663068 was generally well tolerated at all doses and there were no signals of safety issues.

Injectable pre-exposure prophylaxis (PrEP) could be possible, new research involving monkeys suggests. Two separate studies showed that injecting the investigational integrase inhibitor GSK744LA provided long-lasting protection against HIV. In one study, a single dose was protective for an average of eight weeks. Results of a second study showed that none of the monkeys given the drug became infected when exposed to SHIV (a virus that mimics the course of HIV infection in monkeys), and drug levels remained at potentially protective levels up to five weeks after the last injection. On the basis of these results, investigators suggested that monthly injections with the product could be enough to protect against infection with HIV. The first human studies assessing the efficacy of injected GSK744LA as PrEP for humans will start this year.

Achieving the goal of the end of AIDS will require the transformation of the HIV epidemic into low level endemic in most regions of the world over the next 10-15 years. To achieve the end of AIDS we need to build on successes, learn from failures and implement to scale all the strategic and core interventions that over the last decade science has taught us. These include:
Know your epidemic – have detailed understanding of local epidemiology

The HIV epidemic varies considerably between regions and even within countries. A good example of how HIV prevalence varies between states and between Local Governments in Nigeria is illustrated in figure 3.

A detailed understanding of the local epidemiology will enable each country to develop appropriate interventions that respond specifically to their communities’ needs. The strong geographical variation in HIV prevalence within countries should be strategically used for commitment of resources for focused programmes in high prevalence zones. “Knowing your epidemic” is essential for all countries, even those with stable and declining epidemics to identify “hotspots”

Scale up of HIV prevention

Several effective HIV prevention options including combination prevention are already available for reducing new HIV infections but are not being implemented at the necessary scale and magnitude to those who need it most. Figure 8 provides from modelling of the potential impact of tackling individual HIV prevention options to scale in Nigeria. The gaps in current prevention options include:
•HIV counselling and testing – It is estimated that in most middle and low income countries including Nigeria, more than 40% of individuals who are HIV positive may not be aware of their status thereby posing great dangers to transmitting the virus within their sexual contacts.

This is more so in vulnerable and marginalized groups like sex workers and MSM, who have high HIV prevalence. Innovative means of how to reach these group and others reluctant to test must be devised given the importance of HIV testing as a gateway to both prevention and treatment.
•MTCT (breastfeeding transmission and reaching those mothers who do not attend antenatal care). The number of pregnant women living with HIV who received antiretroviral in 2012 (900,000 worldwide) increased, with coverage rising from 57% in 2011 to 63% in 2012. In Nigeria, only 58% of women attend ANC for the first time and retention in care and delivery in facilities has been a great challenge with only about 40% of women going on to deliver in health facilities.

The majority of women opt to deliver with Traditional Birth Attendants (TBAs), in churches and mosques and at home. Strategies must be developed to mobilize women to attend ANC and access PMTCT services or get them tested in the community and link them with ANC services at secondary or primary health clinics located within their communities.
•Circumcision – providing circumcision scale up and creating demand. Male circumcision has become a simple procedure that can be carried out in field settings. WHO and UNAIDS have developed guidelines that will assist in reducing the risk of acquiring HIV in adult males. The procedure takes 20 to 30 minutes. In view of the slow pace in the scale up of the procedure, considerable shifts in culture and social norms are needed to increase the demand for adult male circumcision significantly.
•Injecting drug use and the need to overcome stigma and discrimination among this group. Also it will be very necessary to map out the location and size of the group and as part of the prevention package to this key population, the provision of methadone and clean needles.
•Need to implement new technologies like Pre-Exposure Prophylaxis (PrEP) and Treatment as Prevention (TasP, Test and Treat) in a targeted manner as part of a comprehensive HIV prevention approach (condoms, needle exchange, risk reduction etc.). Nigeria is currently being supported through a grant from the Bill and Melinda Gates Foundation to the National Agency for the Control of AIDS (NACA) to implement a Demonstration study on PrEP among sero-discordant couples in four states – Plateau, Benue, Anambra and Abia states.
•Importance of focusing resources that target key populations that have not been able to achieve low incidence, for example adolescents and young girls in particular. In this regard, through the leadership of NACA and UNICEF, Nigeria has developed a strategic framework for engaging adolescents and young girls. Implementation of this strategy in this key population will not only reduce new infections but also create a pool of young people who will lead the fight among young people in the country.
•Targeting young people, including comprehensive sexual and reproductive health education in schools before they become sexually active. In this regard, it will be essential that the Federal Ministry of Education take the lead in scaling up the Family Life and HIV Education (FLHE) in schools and using the already existing platform of the National Youth Service Corp (NYSC) HIV and AIDS program to expand the peer education and reproductive health education to secondary schools in all states of the country.

Scale up of HIV treatment
New WHO ART guidelines, released in June 2013, recommend earlier initiation of ART and use of simplified, more durable regimens. For many people living with HIV, treatment is now medically indicated immediately upon HIV diagnosis, regardless of CD4 count. The new guidelines, which aim to maximize the therapeutic and preventive benefits of ART, increased the estimated number of people eligible for ART from roughly 15 million to 26 million.

We have eight months to reach the global target of 15 million people on antiretroviral therapy by 2015. By the end of 2012 almost 10 million people were benefiting from these lifesaving drugs in middle and low income countries. In Nigeria, over 650,000 PLWHV are accessing ART in more than 500 centres. There are plans in the PCRP to expand the coverage of antiretroviral treatment to 1.2 million adults and children by 2017 through the establishment of additional 2000 treatment sites.

This will amount to significant progress not only seen in Nigeria but in many low and middle income countries. This has led in a growing number of countries to the laying the foundation and the groundwork for ending the AIDS epidemic by scaling up HIV treatment combined with other essential prevention and control activities. However, millions still are in need of treatment. A recent review of prevention interventions observed that among biomedical interventions tools evaluated, effective antiretroviral treatment provides the greatest prevention effect, as it provides a dual effect of saving the lives of people living with HIV and sharply interrupting the transmission of HIV within the community.

One key issue has remained the issue of maintaining people on ART and ensuring that they have adequate adherence to the drugs in order to achieve virologic suppression and durability. AIDS treatment is not a cure and for an effective viral suppression, individuals receiving treatment must have an adherence of 95% or risk the development of resistance to the drugs. The use of treatment support partners within the family and community has been found helpful in promoting adherence amongst patients. Patients who fail the first line drugs are switched to second line drugs, which are often more complex and more toxic than first line drugs.

In addition, second and third line drugs are much more costly and hence all efforts must be made to ensure adherence to the first line regimen and prevent loss to follow up. Various strategies have been used to assist with adherence; ranging from the use of alarms, to

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